8-50450727-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_018967.5(SNTG1):c.361G>C(p.Val121Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00185 in 1,612,744 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (0 hom.)
• Consequence: SNTG1 NM_018967.5 missense, splice_region
• Scores: Splicing: ADA: 0.8942
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.58

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.018587768).
• BP6: Variant 8-50450727-G-C is Benign according to our data. Variant chr8-50450727-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 3055929.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNTG1	NM_018967.5	c.361G>C	p.Val121Leu	missense_variant, splice_region_variant	8/19	ENST00000642720.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNTG1	ENST00000642720.2	c.361G>C	p.Val121Leu	missense_variant, splice_region_variant	8/19		NM_018967.5	P1

Frequencies

GnomAD3 genomes AF: 0.00168 AC: 256 AN: 152164 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00285

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00148 AC: 370 AN: 250514 Hom.: 0 AF XY: 0.00159 AC XY: 215 AN XY: 135458

Gnomad AFR exome AF: 0.000371

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.00238

Gnomad OTH exome AF: 0.00295

GnomAD4 exome AF: 0.00187 AC: 2724 AN: 1460462 Hom.: 0 Cov.: 32 AF XY: 0.00183 AC XY: 1332 AN XY: 726568

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00168

Gnomad4 ASJ exome AF: 0.00107

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000320

Gnomad4 NFE exome AF: 0.00219

Gnomad4 OTH exome AF: 0.00232

GnomAD4 genome AF: 0.00168 AC: 256 AN: 152282 Hom.: 1 Cov.: 33 AF XY: 0.00161 AC XY: 120 AN XY: 74454

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00285

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00227 Hom.: 0

Bravo AF: 0.00176

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00126 AC: 153

Asia WGS AF: 0.00144 AC: 5 AN: 3476

EpiCase AF: 0.00300

EpiControl AF: 0.00285

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

SNTG1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 27, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.13
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Benign	0.028	T;T;.;.;.;T;.;.;.;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.019	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.1	M;M;.;.;.;M;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-2.1	N;.;.;.;.;N;.;N;.;.;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.017	D;.;.;.;.;D;.;D;.;.;.
Sift4G	Uncertain	0.022	D;.;.;.;.;D;.;D;.;.;.
Polyphen		0.92	P;P;.;.;.;P;.;D;.;.;.
Vest4		0.66
MutPred		0.73		Loss of catalytic residue at V121 (P = 0.3687);Loss of catalytic residue at V121 (P = 0.3687);.;Loss of catalytic residue at V121 (P = 0.3687);.;Loss of catalytic residue at V121 (P = 0.3687);Loss of catalytic residue at V121 (P = 0.3687);Loss of catalytic residue at V121 (P = 0.3687);Loss of catalytic residue at V121 (P = 0.3687);Loss of catalytic residue at V121 (P = 0.3687);Loss of catalytic residue at V121 (P = 0.3687);
MVP		0.52
MPC		0.20
ClinPred		0.030	T
GERP RS		5.4
Varity_R		0.44
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.89
dbscSNV1_RF	Pathogenic	0.77
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

Publications

LitVar

Other links and lift over

dbSNP: rs138262840; hg19: chr8-51363287; COSMIC: COSV105101011; COSMIC: COSV105101011;