chr20-33439020-C-T

Variant names:

• chr20-33439020-C-T
• rs75025585
• NM_003098.3:c.317G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003098.3(SNTA1):​c.317G>A​(p.Arg106Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00197 in 1,613,974 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R106W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0084 (10 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (16 hom.)
• Consequence: SNTA1 NM_003098.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.67
• Publications: 7 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00801605).
• BP6: Variant 20-33439020-C-T is Benign according to our data. Variant chr20-33439020-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 191576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00837 (1274/152256) while in subpopulation AFR AF = 0.0258 (1070/41548). AF 95% confidence interval is 0.0245. There are 10 homozygotes in GnomAd4. There are 639 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1274 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003098.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNTA1	NM_003098.3	MANE Select	c.317G>A	p.Arg106Gln	missense	Exon 2 of 8	NP_003089.1
	SNTA1	NM_001424413.1		c.317G>A	p.Arg106Gln	missense	Exon 2 of 8	NP_001411342.1
	SNTA1	NM_001424414.1		c.317G>A	p.Arg106Gln	missense	Exon 2 of 8	NP_001411343.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNTA1	ENST00000217381.3	TSL:1 MANE Select	c.317G>A	p.Arg106Gln	missense	Exon 2 of 8	ENSP00000217381.2
	SNTA1	ENST00000953204.1		c.317G>A	p.Arg106Gln	missense	Exon 2 of 9	ENSP00000623263.1
	SNTA1	ENST00000953205.1		c.317G>A	p.Arg106Gln	missense	Exon 2 of 9	ENSP00000623264.1

Frequencies

GnomAD3 genomes AF: 0.00839 AC: 1276 AN: 152138 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.0259

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0103

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00291 AC: 732 AN: 251456 AF XY: 0.00241

Gnomad AFR exome AF: 0.0258

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00956

Gnomad NFE exome AF: 0.000484

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00130 AC: 1904 AN: 1461718 Hom.: 16 Cov.: 32 AF XY: 0.00118 AC XY: 857 AN XY: 727170

African (AFR) AF: 0.0293 AC: 981 AN: 33470

American (AMR) AF: 0.00121 AC: 54 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86242

European-Finnish (FIN) AF: 0.00854 AC: 456 AN: 53414

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.000232 AC: 258 AN: 1111874

Other (OTH) AF: 0.00247 AC: 149 AN: 60390

GnomAD4 genome AF: 0.00837 AC: 1274 AN: 152256 Hom.: 10 Cov.: 33 AF XY: 0.00858 AC XY: 639 AN XY: 74444

African (AFR) AF: 0.0258 AC: 1070 AN: 41548

American (AMR) AF: 0.00347 AC: 53 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0103 AC: 109 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000470 AC: 32 AN: 68018

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00208 Hom.: 13

Bravo AF: 0.00900

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0234 AC: 103

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00322 AC: 391

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Long QT syndrome (1)
-	-	1	Long QT syndrome 12 (1)
-	-	1	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.67
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.076
Eigen_PC	Benign	0.042
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.7
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.071
Sift	Benign	0.061	T
Sift4G	Benign	0.10	T
Polyphen		0.020	B
Vest4		0.28
MVP		0.35
MPC		0.38
ClinPred		0.012	T
GERP RS		4.0
Varity_R		0.16
gMVP		0.27
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs75025585; hg19: chr20-32026826;