Human Gene Module / Chromosome 17 / SMG6

SMG6SMG6, nonsense mediated mRNA decay factor

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 5
Rare Variants / Common Variants
10 / 0
Aliases
SMG6, C17orf31,  EST1A,  SMG-6,  hSMG5/7a
Associated Syndromes
-
Chromosome Band
17p13.3
Associated Disorders
ASD
Relevance to Autism

Duplications involving SMG6 were statistically enriched (P=0.003373) in a cohort of 57,356 patients with neurodevelopmental disorders compared to a cohort of 20,474 controls and were identified in two cases with autism and developmental delay (Nguyen et al., 2013).

Molecular Function

This gene encodes a component of the telomerase ribonucleoprotein complex responsible for the replication and maintenance of chromosome ends. The encoded protein also plays a role in the nonsense-mediated mRNA decay (NMD) pathway, providing the endonuclease activity near the premature translation termination codon that is needed to initiate NMD.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to SMG6 (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Contribution of copy number variants involving nonsense-mediated mRNA decay pathway genes to neuro-developmental disorders Nguyen LS , et al. (2013) No ASD
2 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Support - Zhou X et al. (2022) Yes -
4 Support - Cirnigliaro M et al. (2023) Yes -
5 Support - Soo-Whee Kim et al. (2024) Yes -
Rare Variants   (10)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain De novo - Unknown 23376982 Nguyen LS , et al. (2013)
c.1372C>T p.Pro458Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
- - copy_number_gain Familial Maternal Unknown 23376982 Nguyen LS , et al. (2013)
c.3475G>A p.Val1159Ile missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1275A>G p.Pro425%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.365C>T p.Pro122Leu missense_variant De novo - - 39334436 Soo-Whee Kim et al. (2024)
c.2609C>A p.Ser870Tyr missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.2960C>T p.Thr987Ile missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.238A>G p.Asn80Asp missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.2455C>T p.Gln819Ter stop_gained Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Duplications involving SMG6 were statistically enriched (P=0.003373) in a cohort of 57,356 patients with neurodevelopmental disorders compared to a cohort of 20,474 controls and were identified in two cases with autism and developmental delay (Nguyen et al., 2013). A novel de novo missense variant that was predicted to be possibly damaging was identified in the SMG6 gene in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014.

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

Duplications involving SMG6 were statistically enriched (P=0.003373) in a cohort of 57,356 patients with neurodevelopmental disorders compared to a cohort of 20,474 controls and were identified in two cases with autism and developmental delay (Nguyen et al., 2013). A novel de novo missense variant that was predicted to be possibly damaging was identified in the SMG6 gene in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Duplications involving SMG6 were statistically enriched (P=0.003373) in a cohort of 57,356 patients with neurodevelopmental disorders compared to a cohort of 20,474 controls and were identified in two cases with autism and developmental delay (Nguyen et al., 2013). A novel de novo missense variant that was predicted to be possibly damaging was identified in the SMG6 gene in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014.

Reports Added
[New Scoring Scheme]
10/1/2017
icon
4

Increased from to 4

Description

Duplications involving SMG6 were statistically enriched (P=0.003373) in a cohort of 57,356 patients with neurodevelopmental disorders compared to a cohort of 20,474 controls and were identified in two cases with autism and developmental delay (Nguyen et al., 2013). A novel de novo missense variant that was predicted to be possibly damaging was identified in the SMG6 gene in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014.

Krishnan Probability Score

Score 0.49079021952176

Ranking 5970/25841 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 0.99993513642064

Ranking 615/18225 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 0.94841929631458

Ranking 17676/18665 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
Larsen Cumulative Evidence Score

Score 2

Ranking 408/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score 0.14103376510985

Ranking 5340/20870 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
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
HAO2 Hydroxyacid oxidase 2 Human Protein Binding 51179 Q9NYQ3
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