1-212961227-C-A

Variant names:

• chr1-212961227-C-A
• rs771662401
• NM_001301056.2:c.338C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001301056.2(VASH2):​c.338C>A​(p.Ala113Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: VASH2 NM_001301056.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.48

Genes affected

VASH2 (HGNC:25723): (vasohibin 2) Enables actin binding activity; metallocarboxypeptidase activity; and microtubule binding activity. Involved in axon development and proteolysis. Acts upstream of or within cell-cell fusion; positive regulation of angiogenesis; and positive regulation of endothelial cell proliferation. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VASH2	NM_001301056.2	c.338C>A	p.Ala113Glu	missense_variant	Exon 3 of 8	ENST00000517399.3	NP_001287985.1
VASH2	NM_024749.5	c.338C>A	p.Ala113Glu	missense_variant	Exon 3 of 6		NP_079025.2
VASH2	NM_001136474.3	c.143C>A	p.Ala48Glu	missense_variant	Exon 4 of 9		NP_001129946.1
VASH2	NM_001136475.3	c.26C>A	p.Ala9Glu	missense_variant	Exon 2 of 7		NP_001129947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VASH2	ENST00000517399.3	c.338C>A	p.Ala113Glu	missense_variant	Exon 3 of 8	1	NM_001301056.2	ENSP00000428324.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251464 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135902

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461862 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.338C>A (p.A113E) alteration is located in exon 3 (coding exon 2) of the VASH2 gene. This alteration results from a C to A substitution at nucleotide position 338, causing the alanine (A) at amino acid position 113 to be replaced by a glutamic acid (E). 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	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	.;.;.;.;.;T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	.;D;D;D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.73	D;D;D;D;D;D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.3	.;.;M;M;.;M
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.9	N;N;.;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.088	T;T;.;T;T;T
Sift4G	Benign	0.74	T;T;T;D;T;T
Polyphen		1.0	.;.;D;D;.;D
Vest4		0.83
MutPred		0.53		.;.;Loss of MoRF binding (P = 0.0689);Loss of MoRF binding (P = 0.0689);.;Loss of MoRF binding (P = 0.0689);
MVP		0.28
MPC		1.1
ClinPred		0.90	D
GERP RS		5.0
Varity_R		0.61
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs771662401; hg19: chr1-213134569; COSMIC: COSV55119439;