13-41960991-C-A

Variant names:

• chr13-41960991-C-A
• rs773219232
• NM_015058.2:c.25G>T

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.25G>T​(p.Gly9Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000804 in 1,243,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. G9R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.0e-7 (0 hom.)
• Consequence: VWA8 NM_015058.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.10
• 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=0.2195754).

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.25G>T	p.Gly9Trp	missense	Exon 1 of 45	NP_055873.1	A3KMH1-1
	VWA8	NM_001009814.2		c.25G>T	p.Gly9Trp	missense	Exon 1 of 26	NP_001009814.1	A3KMH1-2
	VWA8-AS1	NR_039974.1		n.-178C>A		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.25G>T	p.Gly9Trp	missense	Exon 1 of 45	ENSP00000368612.3	A3KMH1-1
	VWA8	ENST00000281496.6	TSL:1	c.25G>T	p.Gly9Trp	missense	Exon 1 of 26	ENSP00000281496.6	A3KMH1-2
	VWA8	ENST00000938853.1		c.25G>T	p.Gly9Trp	missense	Exon 1 of 45	ENSP00000608912.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.04e-7 AC: 1 AN: 1243978 Hom.: 0 Cov.: 31 AF XY: 0.00000165 AC XY: 1 AN XY: 606276

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24768

American (AMR) AF: 0.00 AC: 0 AN: 14170

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18258

East Asian (EAS) AF: 0.0000361 AC: 1 AN: 27694

South Asian (SAS) AF: 0.00 AC: 0 AN: 58152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3582

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1015642

Other (OTH) AF: 0.00 AC: 0 AN: 51288

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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	0.30
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	18
DANN	Benign	0.92
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		-1.1
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.10
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.011	D
Polyphen		0.99	D
Vest4		0.50
MutPred		0.39		Gain of catalytic residue at L7 (P = 0.008)
MVP		0.040
MPC		0.063
ClinPred		0.75	D
GERP RS		-0.71
PromoterAI		0.040	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.069
gMVP		0.41
Mutation Taster		=86/14	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: rs773219232; hg19: chr13-42535127;