Genetic Variant VSTM2B:p.Asp36Tyr (chr19-29527234-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001146339.2(VSTM2B):c.106G>T(p.Asp36Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000215 in 1,397,352 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D36N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 1 hom. )

Consequence

VSTM2B
NM_001146339.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.11

Publications

0 publications found

Variant links:

Genes affected

VSTM2B (HGNC:33595): (V-set and transmembrane domain containing 2B) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

VSTM2B links:

VSTM2B-DT (HGNC:27615): (VSTM2B divergent transcript)

VSTM2B-DT links:

LOC124904683 (HGNC:):

LOC124904683 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.795

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VSTM2B	NM_001146339.2 link	c.106G>T	p.Asp36Tyr	missense_variant	Exon 2 of 5	ENST00000335523.8	NP_001139811.1	A6NLU5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
VSTM2B	ENST00000335523.8 link	c.106G>T	p.Asp36Tyr	missense_variant	Exon 2 of 5	5	NM_001146339.2	ENSP00000335038.6	A6NLU5
VSTM2B-DT	ENST00000804084.1 link	n.116+1807C>A		intron_variant	Intron 1 of 4
VSTM2B-DT	ENST00000804085.1 link	n.116+1807C>A		intron_variant	Intron 1 of 3
VSTM2B-DT	ENST00000804102.1 link	n.103+1478C>A		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000129

AC:

AN:

154874

AF XY:

0.0000243

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000215

AC:

AN:

1397352

Hom.:

Cov.:

AF XY:

0.00000435

AC XY:

AN XY:

689170

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31486

American (AMR)

AF:

0.00

AC:

AN:

35644

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25142

East Asian (EAS)

AF:

0.00

AC:

AN:

35648

South Asian (SAS)

AF:

0.0000380

AC:

AN:

78974

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078428

Other (OTH)

AF:

0.00

AC:

AN:

57938

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.79

MetaSVM

Uncertain

0.36

MutationAssessor

Uncertain

2.5

PhyloP100

8.1

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-6.8

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.80

MutPred

0.51

Loss of disorder (P = 0.0266);

MVP

0.54

ClinPred

0.98

GERP RS

3.5

Varity_R

0.85

gMVP

0.74

Mutation Taster

=21/79

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over