1-212988520-T-C

Position:

• chr1-212988520-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001301056.2(VASH2):​c.1004T>C​(p.Leu335Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VASH2 NM_001301056.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.86

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.091550976).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VASH2	NM_001301056.2	c.1004T>C	p.Leu335Pro	missense_variant	8/8	ENST00000517399.3
VASH2	NM_024749.5	c.872T>C	p.Leu291Pro	missense_variant	6/6
VASH2	NM_001136474.3	c.809T>C	p.Leu270Pro	missense_variant	9/9
VASH2	NM_001136475.3	c.692T>C	p.Leu231Pro	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VASH2	ENST00000517399.3	c.1004T>C	p.Leu335Pro	missense_variant	8/8	1	NM_001301056.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Sep 29, 2023

The c.872T>C (p.L291P) alteration is located in exon 6 (coding exon 5) of the VASH2 gene. This alteration results from a T to C substitution at nucleotide position 872, causing the leucine (L) at amino acid position 291 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	0.082
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.030	.;.;.;.;T
Eigen	Benign	-0.23
Eigen_PC	Benign	0.030
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.72	.;T;T;T;T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.092	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	.;.;.;.;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.45	N;N;N;N;N
REVEL	Benign	0.060
Sift	Benign	0.26	T;T;T;T;T
Sift4G	Benign	0.29	T;T;T;T;T
Polyphen		0.0020, 0.0010	.;.;B;.;B
Vest4		0.28
MutPred		0.35		.;.;.;.;Gain of glycosylation at L335 (P = 0.0028);
MVP		0.043
MPC		0.51
ClinPred		0.38	T
GERP RS		5.9
Varity_R		0.18
gMVP		0.24

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-213161862; COSMIC: COSV100853945; COSMIC: COSV100853945;