Human Gene Module / Chromosome 3 / FHIT

FHITfragile histidine triad gene

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
6 / 12
Rare Variants / Common Variants
12 / 3
Aliases
FHIT, FRA3B,  AP3Aase
Associated Syndromes
-
Chromosome Band
3p14.2
Associated Disorders
-
Relevance to Autism

Rare CNVs in the FHIT gene have been identified with autism in AGRE, NIMH and additional cohorts (Sebat et al., 2007).

Molecular Function

Encodes a diadenosine 5',5'''-P1,P3-triphosphate hydrolase involved in purine metabolism.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to FHIT (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Recent Recommendation Expression of common chromosomal fragile site genes, WWOX/FRA16D and FHIT/FRA3B is downregulated by exposure to environmental carcinogens, UV, and BPDE but not by IR Thavathiru E , et al. (2005) No -
2 Recent Recommendation FHIT-proteasome degradation caused by mitogenic stimulation of the EGF receptor family in cancer cells Bianchi F , et al. (2006) No -
3 Primary Strong association of de novo copy number mutations with autism Sebat J , et al. (2007) Yes -
4 Support A discovery resource of rare copy number variations in individuals with autism spectrum disorder Prasad A , et al. (2013) Yes -
5 Support Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder Girirajan S , et al. (2013) Yes -
6 Support Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations Toma C , et al. (2013) Yes -
7 Support Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior Doan RN , et al. (2016) Yes -
8 Positive Association An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype Direk N , et al. (2017) No -
9 Positive Association Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium (2017) Yes -
10 Positive Association Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection Pardias AF , et al. (2018) No -
11 Highly Cited The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers Ohta M , et al. (1996) No -
12 Recent Recommendation Fhit, a putative tumor suppressor in humans, is a dinucleoside 5',5"'-P1,P3-triphosphate hydrolase Barnes LD , et al. (1996) No -
Rare Variants   (12)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
C>T - intergenic_variant - - Unknown 27667684 Doan RN , et al. (2016)
- - copy_number_gain De novo - Simplex 17363630 Sebat J , et al. (2007)
- - copy_number_loss De novo - Simplex 17363630 Sebat J , et al. (2007)
- - copy_number_gain Unknown - Unknown 23275889 Prasad A , et al. (2013)
- - copy_number_loss Unknown - Unknown 23275889 Prasad A , et al. (2013)
delTTTT - intergenic_variant - - Unknown 27667684 Doan RN , et al. (2016)
- - copy_number_loss De novo - Simplex 23375656 Girirajan S , et al. (2013)
delTTTTTTT - intergenic_variant - - Unknown 27667684 Doan RN , et al. (2016)
delTTTTTTTT - intergenic_variant - - Unknown 27667684 Doan RN , et al. (2016)
- - copy_number_loss Familial Unknown Multiplex 23999528 Toma C , et al. (2013)
- - copy_number_loss Familial Maternal Unknown 23275889 Prasad A , et al. (2013)
- - copy_number_gain Familial Maternal Multiplex 23375656 Girirajan S , et al. (2013)
Common Variants   (3)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.103+234744C>G;c.124+234748C>G - intron_variant - - - 28540026 Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium (2017)
c.-163-54381A>G;c.-111+104137A>G - intron_variant - - - 28049566 Direk N , et al. (2017)
c.103+234744C>G;c.124+234748C>G - intron_variant - - - 29483656 Pardias AF , et al. (2018)
SFARI Gene score
2

Strong Candidate

Minimal evidence for the involvement of FHIT in autism comes from one study (Sebat et al.) in which two affected individuals were each found to have a de novo copy number change (one deletion, one duplication) involving the FHIT gene.

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

Minimal evidence for the involvement of FHIT in autism comes from one study (Sebat et al.) in which two affected individuals were each found to have a de novo copy number change (one deletion, one duplication) involving the FHIT gene.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Minimal evidence for the involvement of FHIT in autism comes from one study (Sebat et al.) in which two affected individuals were each found to have a de novo copy number change (one deletion, one duplication) involving the FHIT gene.

Reports Added
[New Scoring Scheme]
4/1/2017
4
icon
4

Decreased from 4 to 4

Description

Minimal evidence for the involvement of FHIT in autism comes from one study (Sebat et al.) in which two affected individuals were each found to have a de novo copy number change (one deletion, one duplication) involving the FHIT gene.

Reports Added
[Strong association of de novo copy number mutations with autism.2007] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations.2013] [The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers.1996] [Fhit, a putative tumor suppressor in humans, is a dinucleoside 5',5'-P1,P3-triphosphate hydrolase.1996] [Expression of common chromosomal fragile site genes, WWOX/FRA16D and FHIT/FRA3B is downregulated by exposure to environmental carcinogens, UV, and ...2005] [FHIT-proteasome degradation caused by mitogenic stimulation of the EGF receptor family in cancer cells.2006] [Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.2016] [An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype.2017] [Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with ...2017]
1/1/2017
4
icon
4

Decreased from 4 to 4

Description

Minimal evidence for the involvement of FHIT in autism comes from one study (Sebat et al.) in which two affected individuals were each found to have a de novo copy number change (one deletion, one duplication) involving the FHIT gene.

Reports Added
[An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype.2017]
10/1/2016
4
icon
4

Decreased from 4 to 4

Description

Minimal evidence for the involvement of FHIT in autism comes from one study (Sebat et al.) in which two affected individuals were each found to have a de novo copy number change (one deletion, one duplication) involving the FHIT gene.

Reports Added
[Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.2016]
7/1/2014
No data
icon
4

Increased from No data to 4

Description

Minimal evidence for the involvement of FHIT in autism comes from one study (Sebat et al.) in which two affected individuals were each found to have a de novo copy number change (one deletion, one duplication) involving the FHIT gene.

4/1/2014
No data
icon
4

Increased from No data to 4

Description

Minimal evidence for the involvement of FHIT in autism comes from one study (Sebat et al.) in which two affected individuals were each found to have a de novo copy number change (one deletion, one duplication) involving the FHIT gene.

Krishnan Probability Score

Score 0.46414038068529

Ranking 9222/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.0013918390045999

Ranking 11547/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.95064385016443

Ranking 18573/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score -0.72093343751927

Ranking 20418/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
External PIN Data
BioGRIDHuman Protein Reference Database
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
FDXR ferredoxin reductase Human Protein Binding 2232 P22570
MTMR6 myotubularin related protein 6 Human Protein Binding 9107 Q9Y217
Submit New Gene

Report an Error