Human Gene Module / Chromosome 4 / ANKRD17

ANKRD17ankyrin repeat domain 17

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
5 / 6
Rare Variants / Common Variants
40 / 0
Aliases
ANKRD17, GTAR,  MASK2,  NY-BR-16
Associated Syndromes
-
Chromosome Band
4q13.3
Associated Disorders
ADHD, ASD, EPS
Relevance to Autism

De novo variants in the ANKRD17 gene, including a frameshift variant and several missense variants, have been identified in ASD probands from the Simons Simplex Collection, the Autism Sequencing Consortium, and AGRE (De Rubeis et al., 2014; Iossifov et al., 2014; Yuen et al., 2017; Satterstrom et al., 2020). Chopra et al., 2021 reported 34 individuals from 32 families with heterozygous ANKRD17 variants and delineated a neurodevelopmental disorder chateracterized by a variable degree of developmental delay/intellectual disability, particularly affecting speech; autism spectrum disorder or autistic features were reported in 8 individuals from this cohort.

Molecular Function

The protein encoded by this gene belongs to the family of ankyrin repeat-containing proteins, and contains two distinct arrays of ankyrin repeats in its amino-terminal region, one with 15 ankyrin repeats, and the other with 10 ankyrin repeats. It also contains a nuclear export signal, nuclear localization signal, and a cyclin-binding RXL motif. Localization of this protein to the nucleus has been shown experimentally, and interactions between this protein and cyclin-dependent kinase 2 have been observed. It has been suggested that this protein plays a role in both DNA replication and in both anti-viral and anti-bacterial innate immune pathways.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ANKRD17 (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
4 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
5 Recent Recommendation - Chopra M et al. (2021) No ASD, ADHD, epilepsy/seizures
6 Support - Zhou X et al. (2022) Yes -
Rare Variants   (40)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 33909992 Chopra M et al. (2021)
c.751C>T p.Arg251Ter stop_gained Unknown - - 33909992 Chopra M et al. (2021)
c.1890+1G>A - splice_site_variant De novo - - 33909992 Chopra M et al. (2021)
c.1958-2A>C - splice_site_variant De novo - - 33909992 Chopra M et al. (2021)
c.2497C>T p.Gln833Ter stop_gained De novo - - 33909992 Chopra M et al. (2021)
c.2718C>A p.Cys906Ter stop_gained De novo - - 33909992 Chopra M et al. (2021)
c.4403T>G p.Leu1468Ter stop_gained De novo - - 33909992 Chopra M et al. (2021)
c.90C>G p.Pro30%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.833G>T p.Gly278Val missense_variant De novo - - 33909992 Chopra M et al. (2021)
c.1185G>A p.Thr395%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.1556T>C p.Leu519Pro missense_variant De novo - - 33909992 Chopra M et al. (2021)
c.2147T>G p.Leu716Arg missense_variant De novo - - 33909992 Chopra M et al. (2021)
c.3359T>G p.Leu1120Arg missense_variant De novo - - 33909992 Chopra M et al. (2021)
c.3557C>G p.Pro1186Arg missense_variant De novo - - 33909992 Chopra M et al. (2021)
c.4091G>C p.Gly1364Ala missense_variant De novo - - 33909992 Chopra M et al. (2021)
c.5638T>C p.Ser1880Pro missense_variant De novo - - 33909992 Chopra M et al. (2021)
c.7300C>G p.Arg2434Gly missense_variant De novo - - 33909992 Chopra M et al. (2021)
c.670G>A p.Ala224Thr missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.90dup p.Ala31ArgfsTer47 frameshift_variant De novo - - 33909992 Chopra M et al. (2021)
c.4461G>A p.Lys1487%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1793dup p.Asp598GlufsTer9 frameshift_variant De novo - - 33909992 Chopra M et al. (2021)
c.3769_3772del p.Thr1257Ter frameshift_variant De novo - - 33909992 Chopra M et al. (2021)
c.5304_5310del p.Asp1770Ter frameshift_variant De novo - - 33909992 Chopra M et al. (2021)
c.6168dup p.Arg2057Ter frameshift_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.7713G>A p.Lys2571%3D synonymous_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.3683del p.Asn1228MetfsTer11 frameshift_variant De novo - - 33909992 Chopra M et al. (2021)
c.4007del p.Cys1336LeufsTer24 frameshift_variant Unknown - - 33909992 Chopra M et al. (2021)
c.5756dup p.Ala1920SerfsTer20 frameshift_variant De novo - - 33909992 Chopra M et al. (2021)
c.4224A>C p.Glu1408Asp missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.6034_6036del p.Thr2012del inframe_deletion De novo - - 25363760 De Rubeis S , et al. (2014)
c.2623G>T p.Glu875Ter stop_gained Familial Maternal Simplex 33909992 Chopra M et al. (2021)
c.4407G>T p.Arg1469Ser missense_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.5360_5363del p.Gln1787ArgfsTer5 frameshift_variant De novo - - 33909992 Chopra M et al. (2021)
c.4341_4344del p.Gln1448LeufsTer12 frameshift_variant De novo - - 33909992 Chopra M et al. (2021)
c.5942_5948del p.Pro1981HisfsTer21 frameshift_variant De novo - - 33909992 Chopra M et al. (2021)
c.6460_6461del p.Pro2154SerfsTer18 frameshift_variant De novo - - 33909992 Chopra M et al. (2021)
c.3751_3758delinsGGAC p.Asn1251GlyfsTer7 frameshift_variant De novo - - 33909992 Chopra M et al. (2021)
c.495_496delinsC p.Arg165SerfsTer3 frameshift_variant Unknown Not maternal - 33909992 Chopra M et al. (2021)
c.1129G>A p.Ala377Thr missense_variant De novo - Multiplex (monozygotic twins) 33909992 Chopra M et al. (2021)
c.2005_2006delinsGCTAATAATGA p.Ser669delinsAlaAsnAsnAsp inframe_indel De novo - - 33909992 Chopra M et al. (2021)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

Score Delta: Score remained at 2S

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.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2022
icon
2S

Increased from to 2S

Krishnan Probability Score

Score 0.56089691066539

Ranking 1306/25841 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 0.99999999964933

Ranking 82/18225 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
Iossifov Probability Score

Score 0.965

Ranking 65/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.92438045912817

Ranking 9977/18665 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 0.45623241879876

Ranking 860/20870 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
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