20-37944173-G-C

Variant names:

• chr20-37944173-G-C
• rs377435668
• NM_080607.3:c.535G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_080607.3(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. 15/22 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 NM_080607.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.192
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080607.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VSTM2L	NM_080607.3	MANE Select	c.535G>C	p.Ala179Pro	missense	Exon 4 of 4	NP_542174.1	Q96N03-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VSTM2L	ENST00000373461.9	TSL:1 MANE Select	c.535G>C	p.Ala179Pro	missense	Exon 4 of 4	ENSP00000362560.4	Q96N03-1
	VSTM2L	ENST00000954389.1		c.523G>C	p.Ala175Pro	missense	Exon 4 of 4	ENSP00000624448.1
	VSTM2L	ENST00000869290.1		c.472G>C	p.Ala158Pro	missense	Exon 3 of 3	ENSP00000539349.1

Frequencies

GnomAD3 genomes AF: 0.000391 AC: 57 AN: 145920 Hom.: 0 Cov.: 28

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

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

African (AFR) AF: 0.0000356 AC: 1 AN: 28100

American (AMR) AF: 0.000151 AC: 5 AN: 33032

Ashkenazi Jewish (ASJ) AF: 0.000296 AC: 6 AN: 20254

East Asian (EAS) AF: 0.000329 AC: 9 AN: 27362

South Asian (SAS) AF: 0.0000127 AC: 1 AN: 78488

European-Finnish (FIN) AF: 0.000196 AC: 7 AN: 35684

Middle Eastern (MID) AF: 0.000244 AC: 1 AN: 4106

European-Non Finnish (NFE) AF: 0.0000788 AC: 78 AN: 990330

Other (OTH) AF: 0.000101 AC: 5 AN: 49356

⚠️ 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.

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

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

African (AFR) AF: 0.000402 AC: 16 AN: 39820

American (AMR) AF: 0.000339 AC: 5 AN: 14760

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3418

East Asian (EAS) AF: 0.00236 AC: 11 AN: 4660

South Asian (SAS) AF: 0.00275 AC: 12 AN: 4356

European-Finnish (FIN) AF: 0.000421 AC: 4 AN: 9494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.000151 AC: 10 AN: 66334

Other (OTH) AF: 0.00 AC: 0 AN: 2024

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.19
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
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs377435668; hg19: chr20-36572575;