1-212961215-A-G

Variant names:

• chr1-212961215-A-G
• rs138725158
• NM_001301056.2:c.326A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001301056.2(VASH2):​c.326A>G​(p.Asp109Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,888 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D109A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: VASH2 NM_001301056.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.84
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30698043).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001301056.2. 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
	VASH2	NM_001301056.2	MANE Select	c.326A>G	p.Asp109Gly	missense	Exon 3 of 8	NP_001287985.1	Q86V25-1
	VASH2	NM_024749.5		c.326A>G	p.Asp109Gly	missense	Exon 3 of 6	NP_079025.2
	VASH2	NM_001136474.3		c.131A>G	p.Asp44Gly	missense	Exon 4 of 9	NP_001129946.1	Q86V25-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VASH2	ENST00000517399.3	TSL:1 MANE Select	c.326A>G	p.Asp109Gly	missense	Exon 3 of 8	ENSP00000428324.1	Q86V25-1
	VASH2	ENST00000366965.6	TSL:1	c.326A>G	p.Asp109Gly	missense	Exon 3 of 6	ENSP00000355932.2	Q86V25-5
	VASH2	ENST00000917486.1		c.326A>G	p.Asp109Gly	missense	Exon 3 of 7	ENSP00000587545.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.4	L
PhyloP100		8.8
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.27
Sift	Uncertain	0.019	D
Sift4G	Benign	0.081	T
Polyphen		0.68	P
Vest4		0.56
MutPred		0.45		Gain of MoRF binding (P = 0.0412)
MVP		0.21
MPC		0.91
ClinPred		0.96	D
GERP RS		5.0
Varity_R		0.56
gMVP		0.63
Mutation Taster		=187/113	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: rs138725158; hg19: chr1-213134557;