rs572545726

Positions:

• chr20-33443400-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.221C>T​(p.Pro74Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00227 in 1,359,300 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 0.0019 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0023 (7 hom.)
• Consequence: SNTA1 NM_003098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 2.61

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=0.006747484).
• BP6: Variant 20-33443400-G-A is Benign according to our data. Variant chr20-33443400-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 263476.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=1, Benign=1}. Variant chr20-33443400-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 296 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SNTA1	NM_003098.3	c.221C>T	p.Pro74Leu	missense_variant	1/8	ENST00000217381.3	NP_003089.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SNTA1	ENST00000217381.3	c.221C>T	p.Pro74Leu	missense_variant	1/8	1	NM_003098.3	ENSP00000217381.2

Frequencies

GnomAD3 genomes AF: 0.00195 AC: 296 AN: 151818 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000857

Gnomad MID AF: 0.00641

Gnomad NFE AF: 0.00337

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00217 AC: 43 AN: 19810 Hom.: 0 AF XY: 0.00226 AC XY: 29 AN XY: 12814

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000631

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000427

Gnomad FIN exome AF: 0.000632

Gnomad NFE exome AF: 0.00409

Gnomad OTH exome AF: 0.00194

GnomAD4 exome AF: 0.00231 AC: 2786 AN: 1207374 Hom.: 7 Cov.: 31 AF XY: 0.00227 AC XY: 1344 AN XY: 590826

Gnomad4 AFR exome AF: 0.000422

Gnomad4 AMR exome AF: 0.000746

Gnomad4 ASJ exome AF: 0.000174

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000551

Gnomad4 FIN exome AF: 0.000907

Gnomad4 NFE exome AF: 0.00261

Gnomad4 OTH exome AF: 0.00210

GnomAD4 genome AF: 0.00195 AC: 296 AN: 151926 Hom.: 1 Cov.: 31 AF XY: 0.00175 AC XY: 130 AN XY: 74260

Gnomad4 AFR AF: 0.000482

Gnomad4 AMR AF: 0.00125

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000857

Gnomad4 NFE AF: 0.00337

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00244 Hom.: 0

Bravo AF: 0.00179

ExAC AF: 0.00103 AC: 37

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome 12 Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Aug 18, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 15, 2021	The SNTA1 c.221C>T; p.Pro74Leu variant (rs572545726) is reported in the literature in combination with the p.Ala257Gly variant in several healthy controls (Cheng 2009). Functional studies suggest that the p.Pro74Leu variant rescues the in vitro channel activity defect of the p.Ala257Gly variant, but has no effect on channel activity on its own (Cheng 2011). The p.Pro74Leu variant is reported in ClinVar (Variation ID: 263476) and is found in the non-Finnish European population with an allele frequency of 0.40% (98/24572 alleles) in the Genome Aggregation Database. The proline at codon 74 is weakly conserved, and computational analyses predict that this variant is neutral (REVEL: 0.055). While the evidence suggests the p.Pro74Leu does not cause disease and may ameliorate the effects of the p.Ala257Gly, given the lack of clinical and functional data, the significance of the p.Pro74Leu variant cannot be determined with certainty. 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. -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 08, 2023	Variant summary: SNTA1 c.221C>T (p.Pro74Leu) results in a non-conservative amino acid change located in the pleckstrin homology domain (IPR001849) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0022 in 20944 control chromosomes. The observed variant frequency is approximately 224.41 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. c.221C>T has been reported in the literature along with another SNTA1 variant, c.770C>G (p.Ala257Gly) in sequencing studies of individuals affected with Arrhythmia and/or in SIDS cohorts (example, Cheng_2009, Broendberg_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmia. 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. These results showed no damaging effect of this variant as it was demonstrated to have a rescue function when present in conjunction with (p.Arg257Gly). 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: 20009079, 25650408, 24319568, 29343803). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign, n=1; likely benign, n=8, VUS, n=1). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jul 09, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

SNTA1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 19, 2020

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). -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Ventricular tachycardia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Sep 15, 2018

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 16, 2018

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	0.084
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.055
Sift	Benign	0.032	D
Sift4G	Benign	0.24	T
Polyphen		0.0	B
Vest4		0.071
MVP		0.52
MPC		0.29
ClinPred		0.026	T
GERP RS		2.5
Varity_R		0.053
gMVP		0.29

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: rs572545726; hg19: chr20-32031206;