dbSNP rs763904112: VSTM2B:p.Ala28Asp (chr19-29527211-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001146339.2(VSTM2B):c.83C>A(p.Ala28Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000717 in 1,395,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. A28G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

VSTM2B
NM_001146339.2 missense, splice_region

Scores

Splicing: ADA: 0.3099

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.03

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.914

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VSTM2B	NM_001146339.2 link	c.83C>A	p.Ala28Asp	missense_variant, splice_region_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.83C>A	p.Ala28Asp	missense_variant, splice_region_variant	Exon 2 of 5	5	NM_001146339.2	ENSP00000335038.6	A6NLU5
VSTM2B-DT	ENST00000804084.1 link	n.116+1830G>T		intron_variant	Intron 1 of 4
VSTM2B-DT	ENST00000804085.1 link	n.116+1830G>T		intron_variant	Intron 1 of 3
VSTM2B-DT	ENST00000804102.1 link	n.103+1501G>T		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.17e-7

AC:

AN:

1395582

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

688222

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31336

American (AMR)

AF:

0.00

AC:

AN:

35560

Ashkenazi Jewish (ASJ)

AF:

0.0000399

AC:

AN:

25074

East Asian (EAS)

AF:

0.00

AC:

AN:

35550

South Asian (SAS)

AF:

0.00

AC:

AN:

78766

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48166

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5688

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1077570

Other (OTH)

AF:

0.00

AC:

AN:

57872

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

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

0.59

BayesDel_addAF

Benign

-0.062

BayesDel_noAF

Benign

-0.33

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.75

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.91

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.8

PhyloP100

4.0

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-4.3

REVEL

Uncertain

0.37

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.81

MutPred

0.73

Gain of relative solvent accessibility (P = 0.0098);

MVP

0.27

ClinPred

0.99

GERP RS

4.5

Varity_R

0.83

gMVP

0.79

Mutation Taster

=26/74

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.31

dbscSNV1_RF

Benign

0.49

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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