rs34995247

Positions:

• chr20-33417865-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003098.3(SNTA1):​c.555C>T​(p.Val185=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00177 in 1,614,030 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0087 (13 hom., cov: 31)
  • Exomes 𝑓: 0.0010 (19 hom.)
• Consequence: SNTA1 NM_003098.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.50

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 20-33417865-G-A is Benign according to our data. Variant chr20-33417865-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 263425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-33417865-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.5 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00871 (1326/152222) while in subpopulation AFR AF= 0.029 (1204/41544). AF 95% confidence interval is 0.0276. There are 13 homozygotes in gnomad4. There are 629 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1326 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SNTA1	NM_003098.3	c.555C>T	p.Val185=	synonymous_variant	3/8	ENST00000217381.3	NP_003089.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SNTA1	ENST00000217381.3	c.555C>T	p.Val185=	synonymous_variant	3/8	1	NM_003098.3	ENSP00000217381	P1

Frequencies

GnomAD3 genomes AF: 0.00870 AC: 1324 AN: 152104 Hom.: 13 Cov.: 31

Gnomad AFR AF: 0.0290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00584

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00911

GnomAD3 exomes AF: 0.00235 AC: 591 AN: 251168 Hom.: 3 AF XY: 0.00174 AC XY: 236 AN XY: 135812

Gnomad AFR exome AF: 0.0290

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00105 AC: 1533 AN: 1461808 Hom.: 19 Cov.: 32 AF XY: 0.000943 AC XY: 686 AN XY: 727218

Gnomad4 AFR exome AF: 0.0315

Gnomad4 AMR exome AF: 0.00228

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000137

Gnomad4 OTH exome AF: 0.00282

GnomAD4 genome AF: 0.00871 AC: 1326 AN: 152222 Hom.: 13 Cov.: 31 AF XY: 0.00845 AC XY: 629 AN XY: 74424

Gnomad4 AFR AF: 0.0290

Gnomad4 AMR AF: 0.00576

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00901

Alfa AF: 0.00388 Hom.: 2

Bravo AF: 0.00998

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 16, 2018	Variant summary: SNTA1 c.555C>T alters a non-conserved nucleotide resulting in a synonymous change. The variant allele was found at a frequency of 0.0027 in 121272 control chromosomes in the ExAC database, including 2 homozygotes. The observed variant frequency is approximately 273.76 fold of 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.555C>T 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. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Long QT syndrome 12 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 21, 2019	- -
Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Congenital long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 06, 2016

This alteration is classified as 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
BayesDel_noAF	Benign	-0.58
CADD	Benign	3.6
DANN	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs34995247; hg19: chr20-32005671;