15-75372158-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BS1_Supporting BS2

The NM_001145358.2(SIN3A):c.3643G>A(p.Asp1215Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000129 in 1,613,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: SIN3A NM_001145358.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.91

Genes affected

SIN3A (HGNC:19353): (SIN3 transcription regulator family member A) 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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SIN3A
• BP4: Computational evidence support a benign effect (MetaRNN=0.14713734).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000112 (17/152148) while in subpopulation NFE AF= 0.000176 (12/68030). AF 95% confidence interval is 0.000102. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIN3A	NM_001145358.2	c.3643G>A	p.Asp1215Asn	missense_variant	21/21	ENST00000394947.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIN3A	ENST00000394947.8	c.3643G>A	p.Asp1215Asn	missense_variant	21/21	1	NM_001145358.2	P4

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000517 AC: 13 AN: 251230 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135812

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000131 AC: 192 AN: 1461838 Hom.: 0 Cov.: 31 AF XY: 0.000114 AC XY: 83 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000169

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74314

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000198 Hom.: 0

Bravo AF: 0.000132

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 28, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1215 of the SIN3A protein (p.Asp1215Asn). This variant is present in population databases (rs757810589, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SIN3A-related conditions. ClinVar contains an entry for this variant (Variation ID: 2185011). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SIN3A protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.36	T;T;T
Eigen	Benign	-0.22
Eigen_PC	Benign	0.0036
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;L;L
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.034
Sift	Benign	0.32	T;T;T
Sift4G	Benign	0.65	T;T;T
Polyphen		0.0050	B;B;B
Vest4		0.36
MVP		0.53
MPC		0.64
ClinPred		0.15	T
GERP RS		5.2
Varity_R		0.087
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs757810589; hg19: chr15-75664499;