rs147964932

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_003098.3(SNTA1):c.1088A>C(p.Glu363Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000284 in 1,611,690 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. E363K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00029 ( 1 hom. )

Consequence

SNTA1
NM_003098.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 7.86

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

long QT syndrome 12
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
long QT syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

SNTA1 links:

LOC124904889 (HGNC:):

LOC124904889 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23189902).

BP6

Variant 20-33410284-T-G is Benign according to our data. Variant chr20-33410284-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 190918.

BS2

High AC in GnomAd4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNTA1	NM_003098.3 link	c.1088A>C	p.Glu363Ala	missense_variant	Exon 6 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.1088A>C	p.Glu363Ala	missense_variant	Exon 6 of 8	1	NM_003098.3	ENSP00000217381.2		Q13424-1
ENSG00000288878	ENST00000785672.1 link	n.224+50T>G		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00165

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000316

AC:

AN:

246978

AF XY:

0.000426

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000584

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000480

Gnomad NFE exome

AF:

0.000188

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.000293

AC:

427

AN:

1459374

Hom.:

Cov.:

AF XY:

0.000325

AC XY:

236

AN XY:

725918

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33402

American (AMR)

AF:

0.0000898

AC:

AN:

44558

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26086

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39652

South Asian (SAS)

AF:

0.00172

AC:

148

AN:

85974

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53266

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4744

European-Non Finnish (NFE)

AF:

0.000228

AC:

253

AN:

1111488

Other (OTH)

AF:

0.000299

AC:

AN:

60204

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

115

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000204

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41566

American (AMR)

AF:

0.000131

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00166

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000294

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000137

Hom.:

Bravo

AF:

0.000113

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000321

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Wolff-Parkinson-White pattern

Uncertain:1

Jul 14, 2017

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

This variant was identified in an individual with Wolff-Parkinson-White syndrome -

not provided

Uncertain:1

Jan 11, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in patients with LQTS in published literature (PMID: 23631430, 36528013); Reported in an individual with a prolonged QTc, ventricular tachycardia, a clinical diagnosis of Marfan syndrome, and a history of sudden cardiac arrest; however, this proband was also found to harbor a de novo TGFBR2 variant, and this proband's unaffected mother was also heterozygous for this SNTA1 variant (PMID: 30158670); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23631430, 36528013, 30158670) -

Long QT syndrome

Uncertain:1

Jul 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 363 of the SNTA1 protein (p.Glu363Ala). This variant is present in population databases (rs147964932, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with long QT syndrome (PMID: 23631430). ClinVar contains an entry for this variant (Variation ID: 190918). 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. -

not specified

Benign:1

Feb 13, 2023

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Long QT syndrome 12

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Cardiovascular phenotype

Benign:1

Oct 18, 2019

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

0.22

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.84

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.23

MetaSVM

Uncertain

0.22

MutationAssessor

Uncertain

2.0

PhyloP100

7.9

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.6

REVEL

Pathogenic

0.75

Sift

Benign

0.13

Sift4G

Benign

0.082

Polyphen

0.99

Vest4

0.73

MVP

0.92

MPC

0.77

ClinPred

0.16

GERP RS

4.9

Varity_R

0.25

gMVP

0.77

Mutation Taster

=47/53

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over