20-33443400-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

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

Scores

1
1
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11

Conservation

PhyloP100: 2.61
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]

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ACMG classification

Classification made for transcript

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
SNTA1NM_003098.3 linkuse as main transcriptc.221C>T p.Pro74Leu missense_variant 1/8 ENST00000217381.3 NP_003089.1 Q13424-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SNTA1ENST00000217381.3 linkuse as main transcriptc.221C>T p.Pro74Leu missense_variant 1/81 NM_003098.3 ENSP00000217381.2 Q13424-1

Frequencies

GnomAD3 genomes
AF:
0.00195
AC:
296
AN:
151818
Hom.:
1
Cov.:
31
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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:1Benign:11
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Long QT syndrome 12 Uncertain:1Benign:2
Likely benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, University Medical Center UtrechtAug 18, 2017- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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 submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesJan 15, 2021The 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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 08, 2023Variant 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 submitterclinical testingMolecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart InstituteJul 09, 2019- -
Benign, criteria provided, single submitterclinical testingGeneDxJun 01, 2015This 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 providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Likely benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
SNTA1-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesOct 19, 2020This 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 22, 2024- -
Ventricular tachycardia Benign:1
Likely benign, criteria provided, single submitterclinical testingCenter for Advanced Laboratory Medicine, UC San Diego Health, University of California San DiegoSep 15, 2018- -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMay 16, 2018This 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs572545726; hg19: chr20-32031206; API