rs73464952

Variant names:

• chr13-41615006-C-G
• rs73464952
• NM_015058.2:c.4690G>C

Your query was ambiguous. Multiple possible variants found:

• chr13-41615006-C-G
• chr13-41615006-C-T
• chr13-41615006-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_015058.2(VWA8):​c.4690G>C​(p.Val1564Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,278 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1564M) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: VWA8 NM_015058.2 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.86
• Publications: 10 publications found

Genes affected

VWA8 (HGNC:29071): (von Willebrand factor A domain containing 8) Predicted to enable ATP binding activity. Located in mitochondrion and peroxisome. [provided by Alliance of Genome Resources, Apr 2022]

VWA8 Gene-Disease associations (from GenCC):

• retinitis pigmentosa 97

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-41615006-C-G is Pathogenic according to our data. Variant chr13-41615006-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 617837.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015058.2. 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
	VWA8	NM_015058.2	MANE Select	c.4690G>C	p.Val1564Leu	missense	Exon 38 of 45	NP_055873.1	A3KMH1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWA8	ENST00000379310.8	TSL:2 MANE Select	c.4690G>C	p.Val1564Leu	missense	Exon 38 of 45	ENSP00000368612.3	A3KMH1-1
	VWA8	ENST00000938853.1		c.4684G>C	p.Val1562Leu	missense	Exon 38 of 45	ENSP00000608912.1
	VWA8	ENST00000941315.1		c.4612G>C	p.Val1538Leu	missense	Exon 37 of 44	ENSP00000611374.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74458

African (AFR) AF: 0.0000241 AC: 1 AN: 41548

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00 Hom.: 8

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Nonsyndromic cleft lip palate (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.50	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.9
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.19
Sift	Benign	0.054	T
Sift4G	Benign	0.076	T
Polyphen		0.79	P
Vest4		0.72
MutPred		0.16		Loss of catalytic residue at T1568 (P = 0.2687)
MVP		0.13
MPC		0.33
ClinPred		0.62	D
GERP RS		6.1
Varity_R		0.16
gMVP		0.64
Mutation Taster		=61/39	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs73464952; hg19: chr13-42189142;