13-41960921-C-G

Variant names:

• chr13-41960921-C-G
• rs966353455
• NM_015058.2:c.95G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015058.2(VWA8):​c.95G>C​(p.Arg32Pro) 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. 14/22 in silico tools predict 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. R32L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VWA8 NM_015058.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.06
• Publications: 0 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-AS1 (HGNC:44270): (VWA8 antisense RNA 1 (head to head))

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09175938).

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.95G>C	p.Arg32Pro	missense	Exon 1 of 45	NP_055873.1	A3KMH1-1
	VWA8	NM_001009814.2		c.95G>C	p.Arg32Pro	missense	Exon 1 of 26	NP_001009814.1	A3KMH1-2
	VWA8-AS1	NR_039974.1		n.-248C>G		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWA8	ENST00000379310.8	TSL:2 MANE Select	c.95G>C	p.Arg32Pro	missense	Exon 1 of 45	ENSP00000368612.3	A3KMH1-1
	VWA8	ENST00000281496.6	TSL:1	c.95G>C	p.Arg32Pro	missense	Exon 1 of 26	ENSP00000281496.6	A3KMH1-2
	VWA8	ENST00000938853.1		c.95G>C	p.Arg32Pro	missense	Exon 1 of 45	ENSP00000608912.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.092	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.1
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.034
Sift	Benign	0.17	T
Sift4G	Benign	0.12	T
Polyphen		0.046	B
Vest4		0.32
MutPred		0.30		Loss of helix (P = 0.0076)
MVP		0.055
MPC		0.076
ClinPred		0.14	T
GERP RS		2.6
PromoterAI		0.057	Neutral
Varity_R		0.29
gMVP		0.44
Mutation Taster		=90/10	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: rs966353455; hg19: chr13-42535057;