rs56157422

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP3BP6

The NM_003098.3(SNTA1):c.770C>T(p.Ala257Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. A257G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

SNTA1
NM_003098.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.26

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:

LOC124904889 (HGNC:):

LOC124904889 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.789

BP6

Variant 20-33412714-G-A is Benign according to our data. Variant chr20-33412714-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 617899.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SNTA1	NM_003098.3 link	c.770C>T	p.Ala257Val	missense_variant	4/8	ENST00000217381.3	NP_003089.1	Q13424-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SNTA1	ENST00000217381.3 link	c.770C>T	p.Ala257Val	missense_variant	4/8	1	NM_003098.3	ENSP00000217381.2		Q13424-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000798

AC:

AN:

250672

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135652

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461304

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726998

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 21, 2024

The p.A257V variant (also known as c.770C>T), located in coding exon 4 of the SNTA1 gene, results from a C to T substitution at nucleotide position 770. The alanine at codon 257 is replaced by valine, an amino acid with similar properties. This variant has been detected in an individual referred for genetic testing with a suspected diagnosis of long QT syndrome; however, details were limited (Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Long QT syndrome 12

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Nov 21, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.012

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.79

MetaSVM

Benign

-0.53

MutationAssessor

Benign

2.0

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.31

Sift

Benign

0.034

Sift4G

Benign

0.12

Polyphen

1.0

Vest4

0.60

MutPred

0.38

Loss of disorder (P = 0.0758);

MVP

0.71

MPC

0.49

ClinPred

0.80

GERP RS

5.0

Varity_R

0.25

gMVP

0.78

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