1-212972767-A-G

Variant names:

• chr1-212972767-A-G
• rs1376176462
• NM_001301056.2:c.685A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001301056.2(VASH2):​c.685A>G​(p.Ile229Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,614,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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. I229T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: VASH2 NM_001301056.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.66

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.042021066).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VASH2	NM_001301056.2	c.685A>G	p.Ile229Val	missense_variant	Exon 6 of 8	ENST00000517399.3	NP_001287985.1
VASH2	NM_024749.5	c.553A>G	p.Ile185Val	missense_variant	Exon 4 of 6		NP_079025.2
VASH2	NM_001136474.3	c.490A>G	p.Ile164Val	missense_variant	Exon 7 of 9		NP_001129946.1
VASH2	NM_001136475.3	c.373A>G	p.Ile125Val	missense_variant	Exon 5 of 7		NP_001129947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VASH2	ENST00000517399.3	c.685A>G	p.Ile229Val	missense_variant	Exon 6 of 8	1	NM_001301056.2	ENSP00000428324.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251340 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135842

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74342

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000577

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

Bravo AF: 0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.553A>G (p.I185V) alteration is located in exon 4 (coding exon 3) of the VASH2 gene. This alteration results from a A to G substitution at nucleotide position 553, causing the isoleucine (I) at amino acid position 185 to be replaced by a valine (V). 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	0.062
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	10
DANN	Benign	0.60
DEOGEN2	Benign	0.063	.;.;.;.;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.76	.;T;T;T;T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.042	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	.;.;.;.;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.35	N;N;N;N;N
REVEL	Benign	0.075
Sift	Benign	0.66	T;T;T;T;T
Sift4G	Benign	0.59	T;T;T;T;T
Polyphen		0.0	.;.;B;.;B
Vest4		0.15
MutPred		0.20		.;.;.;.;Loss of stability (P = 0.1992);
MVP		0.043
MPC		0.26
ClinPred		0.013	T
GERP RS		-0.36
Varity_R		0.047
gMVP		0.24

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

LitVar

Other links and lift over

dbSNP: rs1376176462; hg19: chr1-213146109;