NM_003098.3:c.770C>G

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_003098.3(SNTA1):c.770C>G(p.Ala257Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00217 in 1,613,556 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0022 ( 9 hom. )

Consequence

SNTA1
NM_003098.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:12

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 Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05499947).

BP6

Variant 20-33412714-G-C is Benign according to our data. Variant chr20-33412714-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 191548.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=4, Uncertain_significance=2}. Variant chr20-33412714-G-C is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 295 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNTA1	NM_003098.3 link	c.770C>G	p.Ala257Gly	missense_variant	Exon 4 of 8	ENST00000217381.3	NP_003089.1	Q13424-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNTA1	ENST00000217381.3 link	c.770C>G	p.Ala257Gly	missense_variant	Exon 4 of 8	1	NM_003098.3	ENSP00000217381.2		Q13424-1

Frequencies

GnomAD3 genomes

AF:

0.00194

AC:

295

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00338

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00174

AC:

437

AN:

250672

Hom.:

AF XY:

0.00166

AC XY:

225

AN XY:

135652

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000458

Gnomad FIN exome

AF:

0.000974

Gnomad NFE exome

AF:

0.00335

Gnomad OTH exome

AF:

0.000981

GnomAD4 exome

AF:

0.00220

AC:

3213

AN:

1461298

Hom.:

Cov.:

AF XY:

0.00215

AC XY:

1565

AN XY:

726996

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.000492

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000580

Gnomad4 FIN exome

AF:

0.000981

Gnomad4 NFE exome

AF:

0.00265

Gnomad4 OTH exome

AF:

0.00192

GnomAD4 genome

AF:

0.00194

AC:

295

AN:

152258

Hom.:

Cov.:

AF XY:

0.00175

AC XY:

130

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.000481

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000848

Gnomad4 NFE

AF:

0.00338

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00274

Hom.:

Bravo

AF:

0.00178

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00302

AC:

ExAC

AF:

0.00195

AC:

237

EpiCase

AF:

0.00338

EpiControl

AF:

0.00296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Long QT syndrome 12

Pathogenic:1Uncertain:1Benign:1

Jul 08, 2016

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 15, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SNTA1 c.770C>G; p.Ala257Gly variant (rs56157422) is reported in the literature in individuals affected with long QT syndrome (Wu 2008) and carriers of the variant have been reported to have a slightly longer QTc interval than non-carriers (Ghouse 2015). However, this variant is also reported in healthy controls in combination with p.Pro74Leu (Cheng 2009), and functional studies suggest that the p.Pro74Leu variant rescues altered channel activity of the p.Ala257Gly variant alone (Cheng 2011). The p.Ala257Gly variant is reported in ClinVar (Variation ID: 191548), and is found in the non-Finnish European population with an allele frequency of 0.34% (442/128,676 alleles, including 3 homozygotes) in the Genome Aggregation Database. The alanine at codon 257 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.357). Due to conflicting information, the clinical significance of the p.Ala257Gly variant is uncertain at this time. References: Cheng J et al. Alpha1-syntrophin mutations identified in sudden infant death syndrome cause an increase in late cardiac sodium current. Circ Arrhythm Electrophysiol. 2009 Dec;2(6):667-76. Cheng J et al. LQTS-associated mutation A257G in a1-syntrophin interacts with the intragenic variant P74L to modify its biophysical phenotype. Cardiogenetics. 2011 Oct 25;1(1). pii: 136. Ghouse J et al. Rare genetic variants previously associated with congenital forms of long QT syndrome have little or no effect on the QT interval. Eur Heart J. 2015 Oct 1;36(37):2523-9. Wu G et al. Alpha-1-syntrophin mutation and the long-QT syndrome: a disease of sodium channel disruption. Circ Arrhythm Electrophysiol. 2008 Aug;1(3):193-201. -

Aug 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified

Uncertain:1Benign:2

Nov 22, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SNTA1 c.770C>G (p.Ala257Gly) results in a non-conservative amino acid change located in the Pleckstrin homology domain (IPR001849) 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 0.0022 in 1614256 control chromosomes in the gnomAD database, including 10 homozygotes. The observed variant frequency is approximately 652.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in SNTA1 causing Long QT Syndrome phenotype (3.3e-06). c.770C>G has been reported in the literature along with another SNTA1 variant, c.221C>T (p.Pro74Leu) in sequencing studies of individuals affected with Long QT Syndrome/Arrhythmia and/or in SIDS cohorts (example, Wu_2008, Ghouse_2015, Cheng_2009, Broendberg_2018). These data indicate that the variant may be associated with disease. At-least one co-occurrence with another pathogenic variant causative of Arrhythmia has been observed at our laboratory (KCNQ1 c.1686G>T, p.Arg562Ser), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a gain of function of the cardiac sodium channel (hNav1.5) (Wu_2008). Another study showed no damaging effect of this variant when present in conjunction with p.Pro74Leu. This variant combination reversed the peak sodium current and window current induced by the p.Arg257Gly variant alone (Cheng_2011). The following publications have been ascertained in the context of this evaluation (PMID: 29343803, 20009079, 24319568, 26159999, 23861362, 19684871, 29714131). ClinVar contains an entry for this variant (Variation ID: 191548). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 09, 2019

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 21, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25956966, 24319568, 19684871, 26159999, 16252003, 20009079, 25650408, 28988457, 29714131) -

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Long QT syndrome

Benign:3

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 08, 2024

Dept of Medical Biology, Uskudar University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Criteria: PP3, BS1, BS2 -

Long QT syndrome 1

Benign:1

Aug 22, 2023

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SNTA1-related disorder

Benign:1

Mar 05, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype

Benign:1

May 16, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Benign

0.26

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.75

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.055

MetaSVM

Benign

-0.55

MutationAssessor

Benign

1.8

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.3

REVEL

Uncertain

0.36

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0080

Polyphen

0.96

Vest4

0.88

MVP

0.72

MPC

0.86

ClinPred

0.073

GERP RS

5.0

Varity_R

0.42

gMVP

0.64

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