20-33443400-G-T

Variant names:

• chr20-33443400-G-T
• rs572545726
• NM_003098.3:c.221C>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.221C>A​(p.Pro74His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000828 in 1,207,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P74L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
• Consequence: SNTA1 NM_003098.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.61
• Publications: 0 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=0.17256281).

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.221C>A	p.Pro74His	missense	Exon 1 of 8	NP_003089.1	Q13424-1
	SNTA1	NM_001424413.1		c.221C>A	p.Pro74His	missense	Exon 1 of 8	NP_001411342.1
	SNTA1	NM_001424414.1		c.221C>A	p.Pro74His	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.221C>A	p.Pro74His	missense	Exon 1 of 8	ENSP00000217381.2	Q13424-1
	SNTA1	ENST00000953204.1		c.221C>A	p.Pro74His	missense	Exon 1 of 9	ENSP00000623263.1
	SNTA1	ENST00000953205.1		c.221C>A	p.Pro74His	missense	Exon 1 of 9	ENSP00000623264.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 8.28e-7 AC: 1 AN: 1207386 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 590832

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23706

American (AMR) AF: 0.00 AC: 0 AN: 10724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17270

East Asian (EAS) AF: 0.00 AC: 0 AN: 26578

South Asian (SAS) AF: 0.00 AC: 0 AN: 52656

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28672

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3314

European-Non Finnish (NFE) AF: 0.00000100 AC: 1 AN: 995382

Other (OTH) AF: 0.00 AC: 0 AN: 49084

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	22
DANN	Benign	0.90
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.6
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.028
Sift	Benign	0.077	T
Sift4G	Benign	0.15	T
Polyphen		0.040	B
Vest4		0.11
MutPred		0.18		Loss of glycosylation at P74 (P = 0.0231)
MVP		0.54
MPC		0.36
ClinPred		0.26	T
GERP RS		2.5
PromoterAI		-0.12	Neutral
Varity_R		0.065
gMVP		0.26
Mutation Taster		=81/19	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: rs572545726; hg19: chr20-32031206;