1-212972858-T-C

Variant names:

• chr1-212972858-T-C
• rs922948611
• NM_001301056.2:c.776T>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001301056.2(VASH2):​c.776T>C​(p.Phe259Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: VASH2 NM_001301056.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.85

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3671962).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VASH2	NM_001301056.2	c.776T>C	p.Phe259Ser	missense_variant	Exon 6 of 8	ENST00000517399.3	NP_001287985.1
VASH2	NM_024749.5	c.644T>C	p.Phe215Ser	missense_variant	Exon 4 of 6		NP_079025.2
VASH2	NM_001136474.3	c.581T>C	p.Phe194Ser	missense_variant	Exon 7 of 9		NP_001129946.1
VASH2	NM_001136475.3	c.464T>C	p.Phe155Ser	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.776T>C	p.Phe259Ser	missense_variant	Exon 6 of 8	1	NM_001301056.2	ENSP00000428324.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.644T>C (p.F215S) alteration is located in exon 4 (coding exon 3) of the VASH2 gene. This alteration results from a T to C substitution at nucleotide position 644, causing the phenylalanine (F) at amino acid position 215 to be replaced by a serine (S). 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	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.041	.;.;.;.;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	.;D;D;D;D
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.37	T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.4	.;.;.;.;L
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.86	N;N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.20	T;T;T;T;T
Sift4G	Benign	0.44	T;T;D;T;T
Polyphen		0.88, 0.95	.;.;P;.;P
Vest4		0.67
MutPred		0.34		.;.;.;.;Gain of disorder (P = 0.0017);
MVP		0.068
MPC		1.4
ClinPred		0.79	D
GERP RS		5.3
Varity_R		0.59
gMVP		0.73

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: rs922948611; hg19: chr1-213146200;