GeneBe

SIN3A

protein-coding

SIN3 transcription regulator family member A, the group of SIN3 histone deacetylase complex subunits|EMSY complex

Gene summary

The protein encoded by this gene is a transcriptional regulatory protein. It contains paired amphipathic helix (PAH) domains, which are important for protein-protein interactions and may mediate repression by the Mad-Max complex. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001145358.2

Inheritance

AD

ClinVar variants

P:128U:378B:224

Top phenotype

Witteveen-Kolk syndrome

gnomAD constraint

pLI —, LoF o/e 0.01

Max pathogenic AF

—

Genomic locus

chr15:75,369,379-75,455,842

External References & Databases

Ensembl (ENSG00000169375)NCBI Gene (25942)OMIM (607776)HGNC:19353GenCCUniProt (Q96ST3)AlphaFoldClinVar (SIN3A)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~86.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

SIN3A-related intellectual disability syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0044699

Submitter: Illumina

chromosome 15q24 deletion syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013256

Submitter: Ambry Genetics

SIN3A-related intellectual disability syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0044699

Submitter: G2P

congenital diaphragmatic herniaLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005711

Submitter: Ambry Genetics

SIN3A-related intellectual disability syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0044699

Submitter: ClinGen

Heterozygous loss of *SIN3A* was first highlighted in relation to syndromic intellectual disability in 2016 (PMID: 27399968). This study identified 4 individuals with *de novo* heterozygous 15q24 deletions associated with intellectual disability and dysmorphic facial features. The smallest region of overlap of the deletions was about 200 kb and included the *SIN3A* gene. Additionally, 8 individuals with *SIN3A* loss of function variants (frameshift and nonsense) were identified. Affected individuals with *SIN3A*-related intellectual disability syndrome or Witteveen-Kolk syndrome typically present with characteristic distinctive facial features, microcephaly, short stature, and mildly impaired intellectual development with delayed cognitive and motor development and subtle anomalies on MRI-brain imaging. To date, at least 27 *de novo* unique variants including frameshift, nonsense and missense variants have been reported (PMIDs: 33437032, 36158056). This gene is intolerant to truncating variants, as indicated by its pLI score of 1 in gnomAD (v2.1.1). This gene-disease relationship is supported by studies in mouse models with gene knockdown showing reduction of cortical progenitor neurons, change in neuronal identity, and aberrant corticocortical projections with abnormal axon elongation (PMID: 27399968). In summary, *SIN3A* is definitively associated with SIN3A-related intellectual disability syndrome. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel Expert Panel on 01/19/2022 (SOP Version 9).

SIN3A-related intellectual disability syndrome due to a point mutationSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0044700

Submitter: Orphanet

chromosome 15q24 deletion syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013256

Submitter: Labcorp Genetics (formerly Invitae)

chromosome 15q24 deletion syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013256

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Witteveen-Kolk syndromeAD

Manifestation: Craniofacial; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 27399968Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SIN3A variants in ClinVar

13 Conditions Cataloged
not providedTotal: 623
Inborn genetic diseasesTotal: 124
SIN3A-related intellectual disability syndrome due to a point mutationTotal: 99
not specifiedTotal: 55
SIN3A-related disorderTotal: 35
SIN3A-related intellectual disability syndromeTotal: 6
See casesTotal: 4
Neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001145358.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
4
clinvar
181
clinvar
9
clinvar
 194
missense
11
clinvar
367
clinvar
32
clinvar
2
clinvar
 412
nonsense
31
clinvar
15
clinvar
3
clinvar
 49
start loss
0
frameshift
40
clinvar
19
clinvar
1
clinvar
 60
splice donor/acceptor (+/-2bp)
3
clinvar
9
clinvar
3
clinvar
 15
Total745437821311730

Highest pathogenic variant AF is 6.9707204e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 84 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001145358.2RefSeqNP_001138830.120MANE Select
ENST00000394947.8EnsemblENSP00000378402.320MANE Select
NM_001145357.2RefSeqNP_001138829.120Standard
NM_001437462.1RefSeqNP_001424391.120Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Huntington,s disease - Homo sapiens (human)
  • Thyroid hormone signaling pathway - Homo sapiens (human)
  • Transcriptional misregulation in cancer - Homo sapiens (human)
  • Androgen receptor signaling pathway
  • Retinoblastoma (RB) in Cancer

Biological Process

  • negative regulation of transcription by RNA polymerase II
  • in utero embryonic development
  • activation of innate immune response
  • positive regulation of defense response to virus by host
  • hematopoietic progenitor cell differentiation

Molecular Function

  • transcription regulatory region sequence-specific DNA binding
  • RNA polymerase II activating transcription factor binding
  • RNA polymerase II repressing transcription factor binding
  • chromatin binding
  • DNA-binding transcription factor activity

Cellular Component

  • kinetochore
  • chromatin
  • nucleus
  • nucleoplasm
  • transcription factor complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000394947
Coding exons
20
Length
86464
Individuals with no LoFs
125744
Homozygous LoFs
0
Heterozygous LoFs
3
Defined
125747
p
0.0000119
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense4.393867170.5380.00004038373
Missense (PolyPhen)61239.210.255012972
Synonymous0.1932622660.9850.00001442446
Loss of Function7.50167.40.01480.00000379738

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000620.000062rare
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000180.000018rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Acts as a transcriptional repressor. Corepressor for REST. Interacts with MXI1 to repress MYC responsive genes and antagonize MYC oncogenic activities. Also interacts with MXD1-MAX heterodimers to repress transcription by tethering SIN3A to DNA. Acts cooperatively with OGT to repress transcription in parallel with histone deacetylation. Involved in he control of the circadian rhythms. Required for the transcriptional repression of circadian target genes, such as PER1, mediated by the large PER complex through histone deacetylation. Cooperates with FOXK1 to regulate cell cycle progression probably by repressing cell cycle inhibitor genes expression (By similarity). {ECO:0000250|UniProtKB:Q60520, ECO:0000269|PubMed:12150998}.;

Recessive Scores

pRec
0.372

Intolerance Scores

RVIS EVS
-1.39
RVIS percentile EVS
4.27

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
E
Essential (gene trap)
H
Indispensability pred.
E
Indispensability score
1.00

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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