Variant 20-37944059-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_080607.3(VSTM2L):c.421G>A(p.Glu141Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000959 in 1,460,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

VSTM2L
NM_080607.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.89

Variant links:

Genes affected

VSTM2L (HGNC:16096): (V-set and transmembrane domain containing 2 like) Predicted to enable cell-cell adhesion mediator activity. Involved in negative regulation of neuron apoptotic process. Located in cytoplasm and extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

VSTM2L links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.868

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VSTM2L	NM_080607.3 linkuse as main transcript	c.421G>A	p.Glu141Lys	missense_variant	4/4	ENST00000373461.9	NP_542174.1
VSTM2L	XM_011528530.2 linkuse as main transcript	c.370G>A	p.Glu124Lys	missense_variant	3/3		XP_011526832.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VSTM2L	ENST00000373461.9 linkuse as main transcript	c.421G>A	p.Glu141Lys	missense_variant	4/4	1	NM_080607.3	ENSP00000362560	P1	Q96N03-1
VSTM2L	ENST00000448944.1 linkuse as main transcript	c.370G>A	p.Glu124Lys	missense_variant	3/3	3		ENSP00000406537		Q96N03-2
VSTM2L	ENST00000373459.4 linkuse as main transcript	c.200G>A	p.Arg67Gln	missense_variant	2/2	3		ENSP00000362558		Q96N03-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000811

AC:

AN:

246624

Hom.:

AF XY:

0.00000747

AC XY:

AN XY:

133956

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000181

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000959

AC:

AN:

1460136

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726108

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2022

The c.421G>A (p.E141K) alteration is located in exon 4 (coding exon 4) of the VSTM2L gene. This alteration results from a G to A substitution at nucleotide position 421, causing the glutamic acid (E) at amino acid position 141 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.27

T;.

Eigen

Uncertain

0.63

Eigen_PC

Pathogenic

0.66

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.87

D;D

MetaSVM

Uncertain

-0.055

MutationAssessor

Pathogenic

3.5

M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-4.0

D;D

REVEL

Pathogenic

0.68

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.83

MutPred

0.79

Gain of methylation at E141 (P = 9e-04);.;

MVP

0.47

MPC

0.79

ClinPred

1.0

GERP RS

5.4

Varity_R

0.89

gMVP

0.77

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over