20-33443334-C-G

Position:

chr20-33443334-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000217381.3(SNTA1):c.287G>C(p.Gly96Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000208 in 1,498,186 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. G96S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

SNTA1
ENST00000217381.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 5.52

Variant links:

Genes affected

SNTA1 (HGNC:11167): (syntrophin alpha 1) Syntrophins are cytoplasmic peripheral membrane scaffold proteins that are components of the dystrophin-associated protein complex. This gene is a member of the syntrophin gene family and encodes the most common syntrophin isoform found in cardiac tissues. The N-terminal PDZ domain of this syntrophin protein interacts with the C-terminus of the pore-forming alpha subunit (SCN5A) of the cardiac sodium channel Nav1.5. This protein also associates cardiac sodium channels with the nitric oxide synthase-PMCA4b (plasma membrane Ca-ATPase subtype 4b) complex in cardiomyocytes. This gene is a susceptibility locus for Long-QT syndrome (LQT) - an inherited disorder associated with sudden cardiac death from arrhythmia - and sudden infant death syndrome (SIDS). This protein also associates with dystrophin and dystrophin-related proteins at the neuromuscular junction and alters intracellular calcium ion levels in muscle tissue. [provided by RefSeq, Jan 2013]

SNTA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.25033793).

BS2

High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SNTA1	NM_003098.3 linkuse as main transcript	c.287G>C	p.Gly96Ala	missense_variant	1/8	ENST00000217381.3	NP_003089.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SNTA1	ENST00000217381.3 linkuse as main transcript	c.287G>C	p.Gly96Ala	missense_variant	1/8	1	NM_003098.3	ENSP00000217381	P1	Q13424-1

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

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:

0.000250

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000959

AC:

AN:

114762

Hom.:

AF XY:

0.0000763

AC XY:

AN XY:

65506

show subpopulations

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:

0.000209

Gnomad OTH exome

AF:

0.000335

GnomAD4 exome

AF:

0.000216

AC:

291

AN:

1346068

Hom.:

Cov.:

AF XY:

0.000233

AC XY:

155

AN XY:

666132

show subpopulations

Gnomad4 AFR exome

AF:

0.0000357

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:

0.000263

Gnomad4 OTH exome

AF:

0.000198

GnomAD4 genome

AF:

0.000138

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.0000724

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:

0.000250

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000218

Hom.:

Bravo

AF:

0.000147

ExAC

AF:

0.0000745

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2024	Identified in a patient with a history of recurrent arrhythmias and incidental finding of fenestrated membrane overlying left atrial appendage (PMID: 33070394); this patient also harbored a pathogenic variant in the LMNA gene; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33070394) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 10, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 14, 2019	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 31, 2018

Variant summary: SNTA1 c.287G>C (p.Gly96Ala) results in a non-conservative amino acid change located in the Pleckstrin homology domain and PDZ domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 144728 control chromosomes (gnomAD). The observed variant frequency is more than 10-fold above the estimated maximal expected allele frequency for a pathogenic variant in SNTA1 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.287G>C in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as a VUS possibly benign variant. -

Long QT syndrome 12

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 23, 2021

- -

Long QT syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 25, 2023

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. 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 SNTA1 protein function. ClinVar contains an entry for this variant (Variation ID: 190907). This variant has not been reported in the literature in individuals affected with SNTA1-related conditions. This variant is present in population databases (rs766925398, gnomAD 0.02%). This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 96 of the SNTA1 protein (p.Gly96Ala). -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 19, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.33

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

Eigen

Benign

0.13

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.063

MetaRNN

Benign

0.25

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.1

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-4.5

REVEL

Benign

0.12

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.020

Polyphen

0.0050

Vest4

0.51

MVP

0.36

MPC

0.99

ClinPred

0.50

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.70

gMVP

0.55

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