19-54041035-C-T

Variant names:

• chr19-54041035-C-T
• rs752197748
• NM_198481.4:c.637G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198481.4(VSTM1):​c.637G>A​(p.Ala213Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000893 in 1,455,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: VSTM1 NM_198481.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.987

Genes affected

VSTM1 (HGNC:29455): (V-set and transmembrane domain containing 1) Predicted to enable cytokine activity. Predicted to be involved in immune system process and signal transduction. Predicted to be located in extracellular space. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.081204146).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VSTM1	NM_198481.4	c.637G>A	p.Ala213Thr	missense_variant	Exon 9 of 9	ENST00000338372.7	NP_940883.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VSTM1	ENST00000338372.7	c.637G>A	p.Ala213Thr	missense_variant	Exon 9 of 9	1	NM_198481.4	ENSP00000343366.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000245 AC: 6 AN: 244960 Hom.: 0 AF XY: 0.0000151 AC XY: 2 AN XY: 132832

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000300

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000567

Gnomad SAS exome AF: 0.0000667

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00000902

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000893 AC: 13 AN: 1455286 Hom.: 0 Cov.: 34 AF XY: 0.00000552 AC XY: 4 AN XY: 724106

Gnomad4 AFR exome AF: 0.0000303

Gnomad4 AMR exome AF: 0.0000456

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.0000467

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 09, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.637G>A (p.A213T) alteration is located in exon 9 (coding exon 9) of the VSTM1 gene. This alteration results from a G to A substitution at nucleotide position 637, causing the alanine (A) at amino acid position 213 to be replaced by a threonine (T). 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	Benign	0.077
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	2.6
DANN	Benign	0.55
DEOGEN2	Benign	0.0010	.;T;.;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0070	N
LIST_S2	Benign	0.62	T;.;.;.
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.081	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	.;L;.;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.0	N;N;N;.
REVEL	Benign	0.025
Sift	Benign	0.20	T;T;T;.
Sift4G	Benign	0.23	T;T;T;T
Polyphen		0.79	.;P;.;.
Vest4		0.054, 0.070, 0.077
MutPred		0.23		.;Loss of helix (P = 0.0068);.;.;
MVP		0.12
MPC		0.099
ClinPred		0.034	T
GERP RS		0.51
Varity_R		0.053
gMVP		0.043

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: rs752197748; hg19: chr19-54544289; COSMIC: COSV58074858;