15-75372130-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.3671G>A(p.Arg1224His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,614,026 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1224C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: SIN3A NM_001145358.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.21

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=0.08919093).
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000328 (48/1461888) while in subpopulation SAS AF= 0.0000696 (6/86256). AF 95% confidence interval is 0.00003. There are 0 homozygotes in gnomad4_exome. There are 30 alleles in male gnomad4_exome subpopulation. Median coverage is 31. 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 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIN3A	NM_001145358.2	c.3671G>A	p.Arg1224His	missense_variant	21/21	ENST00000394947.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIN3A	ENST00000394947.8	c.3671G>A	p.Arg1224His	missense_variant	21/21	1	NM_001145358.2	P4

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000557 AC: 14 AN: 251434 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135898

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: 0.0000653

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000328 AC: 48 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.0000413 AC XY: 30 AN XY: 727246

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: 0.0000696

Gnomad4 FIN exome AF: 0.000449

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74332

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000218 Hom.: 0

Bravo AF: 0.0000189

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000824 AC: 10

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

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

Aug 22, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with SIN3A-related conditions. This variant is present in population databases (rs148486660, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1224 of the SIN3A protein (p.Arg1224His). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.49
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.35	T;T;T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.091
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.089	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L;L;L
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.65	N;N;N
REVEL	Benign	0.049
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.12	T;T;T
Polyphen		0.0040	B;B;B
Vest4		0.17
MVP		0.43
MPC		0.80
ClinPred		0.069	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.048
gMVP		0.69

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: rs148486660; hg19: chr15-75664471; COSMIC: COSV51226370; COSMIC: COSV51226370;