rs150576530

chr20-33412697-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4 BP6 BS2

The NM_003098.3(SNTA1):c.787G>T(p.Ala263Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000258 in 1,613,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: SNTA1 NM_003098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:2
• Conservation: PhyloP100: 5.41

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]

LOC124904889 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.34624553).
• BP6: Variant 20-33412697-C-A is Benign according to our data. Variant chr20-33412697-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190914.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=7, Likely_benign=2}.
• BS2: High AC in GnomAd at 76 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNTA1	NM_003098.3	c.787G>T	p.Ala263Ser	missense_variant	4/8	ENST00000217381.3
LOC124904889	XR_007067567.1	n.2739C>A		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNTA1	ENST00000217381.3	c.787G>T	p.Ala263Ser	missense_variant	4/8	1	NM_003098.3	P1

Frequencies

GnomAD3 genomes AF: 0.000499 AC: 76 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000911

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000259 AC: 65 AN: 250866 Hom.: 0 AF XY: 0.000258 AC XY: 35 AN XY: 135736

Gnomad AFR exome AF: 0.0000617

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: 0.000648

Gnomad NFE exome AF: 0.000432

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000233 AC: 341 AN: 1461406 Hom.: 0 Cov.: 33 AF XY: 0.000226 AC XY: 164 AN XY: 727038

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000829

Gnomad4 NFE exome AF: 0.000257

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.000592 AC XY: 44 AN XY: 74360

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.000911

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000550 Hom.: 1

Bravo AF: 0.000140

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000296 AC: 36

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome 12 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Apr 12, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2019	Reported in a male adolescent with lone atrial fibrillation (Husser et al., 2017); Identified independently and in conjunction with additional cardiogenetic variants in individuals referred for arrhythmia genetic testing at GeneDx; segregation data is limited or absent at this time; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 190914; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28837624, 23861362) -

Congenital long QT syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	Aug 08, 2023	Heterozygous variant NM_003098:c.787G>T (p.Ala263Ser) in the SNTA1 gene was found on WES data in female proband (13 y.o., Caucasian) with Long QT syndrome. An additional variant NM_000238:c.2653C>T (p.Arg885Cys) in the KCNH2 gene was found in this proband. This variant is in The Genome Aggregation Database (gnomAD) v2.1.1 with total MAF 0.0004748 (Date of access 08-08-2023). Clinvar contains entry for this variant (Variation ID: 190914). This variant has been reported in 2 studies in patients with variable phenotypes (PMID: 28837624, 23861362). Most in silico predictors show benign result of the protein change (varsome.com). In accordance with ACMG(2015) criteria and enhanced rare variant interpretation in inherited arrhythmias (PMID: 32893267) this variant is classified as Likely benign with following criteria selected: BS1, BP4. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 11, 2017

- -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 06, 2024

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 263 of the SNTA1 protein (p.Ala263Ser). This variant is present in population databases (rs150576530, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with atrial fibrillation (PMID: 28837624). ClinVar contains an entry for this variant (Variation ID: 190914). 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 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. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 20, 2019

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	0.12
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.025
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.13
Sift	Benign	0.16	T
Sift4G	Benign	0.34	T
Polyphen		0.016	B
Vest4		0.70
MVP		0.57
MPC		0.31
ClinPred		0.051	T
GERP RS		5.0
Varity_R		0.14
gMVP		0.50

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: rs150576530; hg19: chr20-32000503;