Genetic Variant NM_080607.3:c.316G>C (chr20-37933563-G-C) – 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_080607.3(VSTM2L):c.316G>C(p.Ala106Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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. A106S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

VSTM2L
NM_080607.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0220

Publications

0 publications found

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 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=0.018540055).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VSTM2L	NM_080607.3 link	c.316G>C	p.Ala106Pro	missense_variant	Exon 3 of 4	ENST00000373461.9	NP_542174.1	Q96N03-1
VSTM2L	XM_011528530.2 link	c.291+1759G>C		intron_variant	Intron 2 of 2		XP_011526832.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
VSTM2L	ENST00000373461.9 link	c.316G>C	p.Ala106Pro	missense_variant	Exon 3 of 4	1	NM_080607.3	ENSP00000362560.4	Q96N03-1
VSTM2L	ENST00000448944.1 link	c.291+1759G>C		intron_variant	Intron 2 of 2	3		ENSP00000406537.1	Q96N03-2
VSTM2L	ENST00000373459.4 link	c.122-10418G>C		intron_variant	Intron 1 of 1	3		ENSP00000362558.4	Q96N03-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459004

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725850

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:

33366

American (AMR)

AF:

0.00

AC:

AN:

44642

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25984

East Asian (EAS)

AF:

0.00

AC:

AN:

39408

South Asian (SAS)

AF:

0.00

AC:

AN:

86222

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53220

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1110254

Other (OTH)

AF:

0.00

AC:

AN:

60164

⚠️ 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: 0.375

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.66

CADD

Benign

9.6

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.0062

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.55

M_CAP

Benign

0.0028

MetaRNN

Benign

0.019

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.60

PhyloP100

0.022

PrimateAI

Benign

0.40

PROVEAN

Benign

1.4

REVEL

Benign

0.028

Sift

Benign

1.0

Sift4G

Benign

0.39

Polyphen

0.0

Vest4

0.17

MutPred

0.34

Gain of relative solvent accessibility (P = 0.0166);

MVP

0.014

MPC

0.24

ClinPred

0.041

GERP RS

-2.5

Varity_R

0.071

gMVP

0.36

Mutation Taster

=68/32

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over