8-50402265-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018967.5(SNTG1):c.83G>A(p.Arg28Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,613,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R28W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: SNTG1 NM_018967.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.90

Genes affected

SNTG1 (HGNC:13740): (syntrophin gamma 1) The protein encoded by this gene is a member of the syntrophin family. Syntrophins are cytoplasmic peripheral membrane proteins that typically contain 2 pleckstrin homology (PH) domains, a PDZ domain that bisects the first PH domain, and a C-terminal domain that mediates dystrophin binding. This family member plays a role in mediating gamma-enolase trafficking to the plasma membrane and in enhancing its neurotrophic activity. Mutations in this gene are associated with idiopathic scoliosis. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40119833).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNTG1	NM_018967.5	c.83G>A	p.Arg28Gln	missense_variant	4/19	ENST00000642720.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNTG1	ENST00000642720.2	c.83G>A	p.Arg28Gln	missense_variant	4/19		NM_018967.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151980 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

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

GnomAD3 exomes AF: 0.0000677 AC: 17 AN: 250942 Hom.: 0 AF XY: 0.0000664 AC XY: 9 AN XY: 135632

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000655

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461358 Hom.: 0 Cov.: 33 AF XY: 0.0000206 AC XY: 15 AN XY: 726992

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151980 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74250

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000491

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 05, 2023

The c.83G>A (p.R28Q) alteration is located in exon 4 (coding exon 2) of the SNTG1 gene. This alteration results from a G to A substitution at nucleotide position 83, causing the arginine (R) at amino acid position 28 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.22	T;T;.;.;T;.;.;.;.;.;.;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.40	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.4	M;M;.;.;M;.;.;M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.1	D;.;.;.;D;.;.;D;.;D;.;.
REVEL	Benign	0.28
Sift	Uncertain	0.0020	D;.;.;.;D;.;.;D;.;D;.;.
Sift4G	Uncertain	0.0080	D;.;.;.;D;.;.;D;.;D;.;.
Polyphen		0.89	P;P;.;.;P;.;.;D;.;.;.;.
Vest4		0.87
MutPred		0.55		Loss of catalytic residue at R28 (P = 0.0447);Loss of catalytic residue at R28 (P = 0.0447);Loss of catalytic residue at R28 (P = 0.0447);Loss of catalytic residue at R28 (P = 0.0447);Loss of catalytic residue at R28 (P = 0.0447);Loss of catalytic residue at R28 (P = 0.0447);Loss of catalytic residue at R28 (P = 0.0447);Loss of catalytic residue at R28 (P = 0.0447);Loss of catalytic residue at R28 (P = 0.0447);Loss of catalytic residue at R28 (P = 0.0447);Loss of catalytic residue at R28 (P = 0.0447);Loss of catalytic residue at R28 (P = 0.0447);
MVP		0.71
MPC		0.21
ClinPred		0.51	D
GERP RS		4.1
Varity_R		0.53
gMVP		0.63

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

Other links and lift over

dbSNP: rs777169778; hg19: chr8-51314825; COSMIC: COSV99383456;