rs573772189

Variant names:

• chr20-33443455-G-A
• rs573772189
• NM_003098.3:c.166C>T

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.166C>T​(p.Pro56Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00105 in 1,366,196 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P56Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0054 (10 hom., cov: 31)
  • Exomes 𝑓: 0.00051 (4 hom.)
• Consequence: SNTA1 NM_003098.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.340
• Publications: 5 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=0.0031163394).
• BP6: Variant 20-33443455-G-A is Benign according to our data. Variant chr20-33443455-G-A is described in ClinVar as Benign. ClinVar VariationId is 139224.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 = 0.0054 (818/151606) while in subpopulation AFR AF = 0.0185 (768/41462). AF 95% confidence interval is 0.0174. There are 10 homozygotes in GnomAd4. There are 379 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 818 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.166C>T	p.Pro56Ser	missense	Exon 1 of 8	NP_003089.1
	SNTA1	NM_001424413.1		c.166C>T	p.Pro56Ser	missense	Exon 1 of 8	NP_001411342.1
	SNTA1	NM_001424414.1		c.166C>T	p.Pro56Ser	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.166C>T	p.Pro56Ser	missense	Exon 1 of 8	ENSP00000217381.2
	SNTA1	ENST00000953204.1		c.166C>T	p.Pro56Ser	missense	Exon 1 of 9	ENSP00000623263.1
	SNTA1	ENST00000953205.1		c.166C>T	p.Pro56Ser	missense	Exon 1 of 9	ENSP00000623264.1

Frequencies

GnomAD3 genomes AF: 0.00538 AC: 815 AN: 151498 Hom.: 10 Cov.: 31

Gnomad AFR AF: 0.0185

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00191

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00624

GnomAD2 exomes AF: 0.000515 AC: 32 AN: 62138 AF XY: 0.000408

Gnomad AFR exome AF: 0.0166

Gnomad AMR exome AF: 0.00111

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.000562

GnomAD4 exome AF: 0.000513 AC: 623 AN: 1214590 Hom.: 4 Cov.: 31 AF XY: 0.000464 AC XY: 276 AN XY: 595410

African (AFR) AF: 0.0179 AC: 443 AN: 24704

American (AMR) AF: 0.00109 AC: 22 AN: 20100

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19746

East Asian (EAS) AF: 0.00 AC: 0 AN: 25462

South Asian (SAS) AF: 0.0000365 AC: 2 AN: 54800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28252

Middle Eastern (MID) AF: 0.00295 AC: 10 AN: 3392

European-Non Finnish (NFE) AF: 0.0000728 AC: 72 AN: 989400

Other (OTH) AF: 0.00152 AC: 74 AN: 48734

GnomAD4 genome AF: 0.00540 AC: 818 AN: 151606 Hom.: 10 Cov.: 31 AF XY: 0.00511 AC XY: 379 AN XY: 74128

African (AFR) AF: 0.0185 AC: 768 AN: 41462

American (AMR) AF: 0.00190 AC: 29 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10376

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67812

Other (OTH) AF: 0.00618 AC: 13 AN: 2104

Alfa AF: 0.00430 Hom.: 1

ExAC AF: 0.000408 AC: 5

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Long QT syndrome 12 (2)
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Long QT syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.34
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.066
Sift	Benign	0.10	T
Sift4G	Benign	0.34	T
Polyphen		0.0	B
Vest4		0.029
MVP		0.22
MPC		0.28
ClinPred		0.0037	T
GERP RS		-1.9
PromoterAI		-0.0050	Neutral
Varity_R		0.058
gMVP		0.37
Mutation Taster		=95/5	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: rs573772189; hg19: chr20-32031261;