20-33443461-C-T

Variant names:

• chr20-33443461-C-T
• rs786205848
• NM_003098.3:c.160G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003098.3(SNTA1):​c.160G>A​(p.Gly54Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 151,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G54R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SNTA1 NM_003098.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.23
• Publications: 4 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18283918).

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.160G>A	p.Gly54Ser	missense	Exon 1 of 8	NP_003089.1
	SNTA1	NM_001424413.1		c.160G>A	p.Gly54Ser	missense	Exon 1 of 8	NP_001411342.1
	SNTA1	NM_001424414.1		c.160G>A	p.Gly54Ser	missense	Exon 1 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.160G>A	p.Gly54Ser	missense	Exon 1 of 8	ENSP00000217381.2
	SNTA1	ENST00000953204.1		c.160G>A	p.Gly54Ser	missense	Exon 1 of 9	ENSP00000623263.1
	SNTA1	ENST00000953205.1		c.160G>A	p.Gly54Ser	missense	Exon 1 of 9	ENSP00000623264.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151454 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1217526 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 597132

African (AFR) AF: 0.00 AC: 0 AN: 24874

American (AMR) AF: 0.00 AC: 0 AN: 20832

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20008

East Asian (EAS) AF: 0.00 AC: 0 AN: 25386

South Asian (SAS) AF: 0.00 AC: 0 AN: 55664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3418

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 990248

Other (OTH) AF: 0.00 AC: 0 AN: 48790

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151454 Hom.: 0 Cov.: 31 AF XY: 0.0000270 AC XY: 2 AN XY: 73968

African (AFR) AF: 0.0000484 AC: 2 AN: 41344

American (AMR) AF: 0.00 AC: 0 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67800

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.58	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.2
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.033
Sift	Benign	0.16	T
Sift4G	Benign	0.17	T
Polyphen		0.74	P
Vest4		0.18
MutPred		0.31		Gain of glycosylation at G54 (P = 0.0054)
MVP		0.52
MPC		0.28
ClinPred		0.47	T
GERP RS		3.6
PromoterAI		-0.0012	Neutral
Varity_R		0.14
gMVP		0.33
Mutation Taster		=63/37	polymorphism

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

Other links and lift over

dbSNP: rs786205848; hg19: chr20-32031267;