15-75372131-G-A

Position:

chr15-75372131-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2

The NM_001145358.2(SIN3A):c.3670C>T(p.Arg1224Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,614,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1224H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

SIN3A
NM_001145358.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 3.56

Variant links:

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]

SIN3A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SIN3A. . Gene score misZ 4.3926 (greater than the threshold 3.09). Trascript score misZ 5.1543 (greater than threshold 3.09). GenCC has associacion of gene with chromosome 15q24 deletion syndrome, SIN3A-related intellectual disability syndrome due to a point mutation, congenital diaphragmatic hernia, SIN3A-related intellectual disability syndrome, autism, susceptibility to, 15.

BP4

Computational evidence support a benign effect (MetaRNN=0.20124009).

BP6

Variant 15-75372131-G-A is Benign according to our data. Variant chr15-75372131-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1424586.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000171 (26/152226) while in subpopulation NFE AF= 0.000279 (19/68022). AF 95% confidence interval is 0.000182. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIN3A	NM_001145358.2 linkuse as main transcript	c.3670C>T	p.Arg1224Cys	missense_variant	21/21	ENST00000394947.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIN3A	ENST00000394947.8 linkuse as main transcript	c.3670C>T	p.Arg1224Cys	missense_variant	21/21	1	NM_001145358.2	P4

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000171

AC:

AN:

251444

Hom.:

AF XY:

0.000169

AC XY:

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000116

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:

0.000299

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000135

AC:

198

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

104

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000158

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000171

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000172

Hom.:

Bravo

AF:

0.000136

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000264

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1224 of the SIN3A protein (p.Arg1224Cys). This variant is present in population databases (rs142724257, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. 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: 1424586). 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

0.12

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

D;D;D

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

.;.;D

M_CAP

Benign

0.020

MetaRNN

Benign

0.20

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.5

L;L;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.6

N;N;N

REVEL

Benign

0.11

Sift

Benign

0.053

T;T;T

Sift4G

Uncertain

0.047

D;D;D

Polyphen

0.96

D;D;D

Vest4

0.46

MVP

0.48

MPC

1.3

ClinPred

0.045

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.14

gMVP

0.82

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over