rs530603992

chr20-33417831-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_003098.3(SNTA1):c.589C>T(p.Arg197Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,613,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. R197L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: SNTA1 NM_003098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 2.08

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026041776).
• BP6: Variant 20-33417831-G-A is Benign according to our data. Variant chr20-33417831-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 180527.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNTA1	NM_003098.3	c.589C>T	p.Arg197Trp	missense_variant	3/8	ENST00000217381.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNTA1	ENST00000217381.3	c.589C>T	p.Arg197Trp	missense_variant	3/8	1	NM_003098.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000658 AC: 10 AN: 152070 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000965

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000151 AC: 38 AN: 251400 Hom.: 0 AF XY: 0.000132 AC XY: 18 AN XY: 135902

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00136

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000486 AC: 71 AN: 1461620 Hom.: 0 Cov.: 32 AF XY: 0.0000385 AC XY: 28 AN XY: 727138

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000705

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152188 Hom.: 0 Cov.: 31 AF XY: 0.0000672 AC XY: 5 AN XY: 74406

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000967

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000141 Hom.: 1

Bravo AF: 0.0000718

ExAC AF: 0.000132 AC: 16

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ventricular fibrillation, paroxysmal familial, type 1 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Sep 24, 2014

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 16, 2016

A variant of uncertain significance has been identified in the SNTA1 gene. The R197W variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R197W variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, however, it was observed in approximately 0.15-0.20% of alleles from individuals of East Asian ancestry in the 1000 Genomes Project and Exome Aggregation Consortium, indicating it may be a rare benign variant in this population. Additionally, this substitution occurs at a position that is not conserved across species and Tryptophan is tolerated at this position in at least two species. Finally, while R197W is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 10, 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	Benign	0.12
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.49
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	0.016
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	0.61	D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.037
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.017	D
Polyphen		0.99	D
Vest4		0.32
MutPred		0.23		Gain of catalytic residue at L195 (P = 0.0143);
MVP		0.57
MPC		0.75
ClinPred		0.11	T
GERP RS		3.6
Varity_R		0.093
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs530603992; hg19: chr20-32005637;