Genetic Variant NM_001146339.2:c.83C>A (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:

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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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001146339.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VSTM2B	NM_001146339.2	MANE Select	c.83C>A	p.Ala28Asp	missense splice_region	Exon 2 of 5	NP_001139811.1	A6NLU5
VSTM2B	NM_001384641.1		c.-56C>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 5	NP_001371570.1
VSTM2B	NM_001384642.1		c.-56C>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 4	NP_001371571.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VSTM2B	ENST00000335523.8	TSL:5 MANE Select	c.83C>A	p.Ala28Asp	missense splice_region	Exon 2 of 5	ENSP00000335038.6	A6NLU5
VSTM2B	ENST00000915703.1		c.83C>A	p.Ala28Asp	missense splice_region	Exon 3 of 7	ENSP00000585762.1
VSTM2B	ENST00000952478.1		c.83C>A	p.Ala28Asp	missense splice_region	Exon 2 of 6	ENSP00000622537.1

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), 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 v4.9

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over