20-37944173-G-C

Position:

• chr20-37944173-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000373461.9(VSTM2L):​c.535G>C​(p.Ala179Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A179T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000089 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: VSTM2L ENST00000373461.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.192

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04957387).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VSTM2L	NM_080607.3	c.535G>C	p.Ala179Pro	missense_variant	4/4	ENST00000373461.9	NP_542174.1
VSTM2L	XM_011528530.2	c.484G>C	p.Ala162Pro	missense_variant	3/3		XP_011526832.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VSTM2L	ENST00000373461.9	c.535G>C	p.Ala179Pro	missense_variant	4/4	1	NM_080607.3	ENSP00000362560.4
VSTM2L	ENST00000373459.4	c.314G>C	p.Arg105Pro	missense_variant	2/2	3		ENSP00000362558.4
VSTM2L	ENST00000448944.1	c.*37G>C		downstream_gene_variant		3		ENSP00000406537.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 57 AN: 145920 Hom.: 0 Cov.: 28 FAILED QC

Gnomad AFR AF: 0.000378

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000407

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00214

Gnomad SAS AF: 0.00275

Gnomad FIN AF: 0.000421

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000151

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000892 AC: 113 AN: 1266712 Hom.: 0 Cov.: 45 AF XY: 0.0000931 AC XY: 58 AN XY: 623220

Gnomad4 AFR exome AF: 0.0000356

Gnomad4 AMR exome AF: 0.000151

Gnomad4 ASJ exome AF: 0.000296

Gnomad4 EAS exome AF: 0.000329

Gnomad4 SAS exome AF: 0.0000127

Gnomad4 FIN exome AF: 0.000196

Gnomad4 NFE exome AF: 0.0000788

Gnomad4 OTH exome AF: 0.000101

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000397 AC: 58 AN: 146028 Hom.: 0 Cov.: 28 AF XY: 0.000309 AC XY: 22 AN XY: 71154

Gnomad4 AFR AF: 0.000402

Gnomad4 AMR AF: 0.000339

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00236

Gnomad4 SAS AF: 0.00275

Gnomad4 FIN AF: 0.000421

Gnomad4 NFE AF: 0.000151

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2021

The c.535G>C (p.A179P) alteration is located in exon 4 (coding exon 4) of the VSTM2L gene. This alteration results from a G to C substitution at nucleotide position 535, causing the alanine (A) at amino acid position 179 to be replaced by a proline (P). 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	Benign	0.065
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	22
DANN	Benign	0.84
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.085
Sift	Benign	0.44	T
Sift4G	Benign	0.23	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.17		Gain of relative solvent accessibility (P = 0.0024);
MVP		0.067
MPC		0.53
ClinPred		0.13	T
GERP RS		2.9
Varity_R		0.25
gMVP		0.32

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

Other links and lift over

dbSNP: rs377435668; hg19: chr20-36572575;