19-54040977-G-A

Variant names:

• chr19-54040977-G-A
• rs146430350
• NM_198481.4:c.695C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_198481.4(VSTM1):​c.695C>T​(p.Ala232Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000036 in 1,609,608 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. 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. A232T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: VSTM1 NM_198481.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.611
• Publications: 4 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.046490967).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198481.4. 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
	VSTM1	NM_198481.4	MANE Select	c.695C>T	p.Ala232Val	missense	Exon 9 of 9	NP_940883.2	Q6UX27-1
	VSTM1	NM_001288792.2		c.602C>T	p.Ala201Val	missense	Exon 8 of 8	NP_001275721.1	Q6UX27-2
	VSTM1	NM_001288791.2		c.431C>T	p.Ala144Val	missense	Exon 9 of 9	NP_001275720.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VSTM1	ENST00000338372.7	TSL:1 MANE Select	c.695C>T	p.Ala232Val	missense	Exon 9 of 9	ENSP00000343366.2	Q6UX27-1
	VSTM1	ENST00000376626.5	TSL:1	c.602C>T	p.Ala201Val	missense	Exon 8 of 8	ENSP00000365813.1	Q6UX27-2
	VSTM1	ENST00000366170.6	TSL:1	c.335C>T	p.Ala112Val	missense	Exon 6 of 6	ENSP00000444153.2	D2DJS5

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152044 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000809 AC: 2 AN: 247146 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000364 AC: 53 AN: 1457564 Hom.: 0 Cov.: 34 AF XY: 0.0000345 AC XY: 25 AN XY: 725140

African (AFR) AF: 0.00 AC: 0 AN: 33110

American (AMR) AF: 0.00 AC: 0 AN: 44198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26042

East Asian (EAS) AF: 0.00 AC: 0 AN: 39238

South Asian (SAS) AF: 0.00 AC: 0 AN: 85834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5324

European-Non Finnish (NFE) AF: 0.0000468 AC: 52 AN: 1110308

Other (OTH) AF: 0.0000166 AC: 1 AN: 60150

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152044 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74244

African (AFR) AF: 0.00 AC: 0 AN: 41390

American (AMR) AF: 0.000131 AC: 2 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	10
DANN	Benign	0.39
DEOGEN2	Benign	0.0042	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.63	N
PhyloP100		0.61
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.022
Sift	Benign	0.43	T
Sift4G	Benign	0.52	T
Polyphen		0.057	B
Vest4		0.091
MutPred		0.34		Gain of sheet (P = 0.0028)
MVP		0.048
MPC		0.10
ClinPred		0.021	T
GERP RS		1.6
Varity_R		0.027
gMVP		0.089
Mutation Taster		=96/4	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: rs146430350; hg19: chr19-54544231; COSMIC: COSV58075032;