Genetic Variant VSTM4:p.Arg244Lys (chr10-49048522-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001031746.5(VSTM4):c.731G>A(p.Arg244Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,448,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

VSTM4
NM_001031746.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.49

Publications

0 publications found

Variant links:

Genes affected

VSTM4 (HGNC:26470): (V-set and transmembrane domain containing 4) Predicted to act upstream of or within several processes, including endothelial cell migration; retina blood vessel maintenance; and vasculature development. Predicted to be located in extracellular region and plasma membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

VSTM4 links:

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ACMG classification

Classification was made for transcript

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=0.045107543).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001031746.5. 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
	VSTM4	NM_001031746.5	MANE Select	c.731G>A	p.Arg244Lys	missense	Exon 6 of 8	NP_001026916.2	Q8IW00-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VSTM4	ENST00000332853.9	TSL:1 MANE Select	c.731G>A	p.Arg244Lys	missense	Exon 6 of 8	ENSP00000331062.3	Q8IW00-1
	VSTM4	ENST00000956395.1		c.944G>A	p.Arg315Lys	missense	Exon 7 of 9	ENSP00000626454.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000420

AC:

AN:

238126

AF XY:

0.00

show subpopulations

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:

0.00000913

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1448184

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720284

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32524

American (AMR)

AF:

0.00

AC:

AN:

42354

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25838

East Asian (EAS)

AF:

0.00

AC:

AN:

38764

South Asian (SAS)

AF:

0.00

AC:

AN:

83396

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53316

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5396

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1106782

Other (OTH)

AF:

0.00

AC:

AN:

59814

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.74

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0071

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.66

M_CAP

Benign

0.0087

MetaRNN

Benign

0.045

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.48

PhyloP100

1.5

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.52

REVEL

Benign

0.13

Sift

Benign

0.25

Sift4G

Benign

0.49

Polyphen

0.0020

Vest4

0.17

MutPred

0.23

Gain of methylation at R244 (P = 0.0055)

MVP

0.25

MPC

0.17

ClinPred

0.23

GERP RS

4.1

Varity_R

0.13

gMVP

0.23

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over