13-41960991-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS2_Supporting

The NM_015058.2(VWA8):​c.25G>A​(p.Gly9Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000804 in 1,243,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000080 (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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06705126).
• BS2: High AC in GnomAdExome4 at 10 Unknown,AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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>A	p.Gly9Arg	missense	Exon 1 of 45	NP_055873.1	A3KMH1-1
	VWA8	NM_001009814.2		c.25G>A	p.Gly9Arg	missense	Exon 1 of 26	NP_001009814.1	A3KMH1-2
	VWA8-AS1	NR_039974.1		n.-178C>T		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>A	p.Gly9Arg	missense	Exon 1 of 45	ENSP00000368612.3	A3KMH1-1
	VWA8	ENST00000281496.6	TSL:1	c.25G>A	p.Gly9Arg	missense	Exon 1 of 26	ENSP00000281496.6	A3KMH1-2
	VWA8	ENST00000938853.1		c.25G>A	p.Gly9Arg	missense	Exon 1 of 45	ENSP00000608912.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000804 AC: 10 AN: 1243980 Hom.: 0 Cov.: 31 AF XY: 0.0000115 AC XY: 7 AN XY: 606276

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: 0.00 AC: 0 AN: 27694

South Asian (SAS) AF: 0.00 AC: 0 AN: 58154

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: 0.00000886 AC: 9 AN: 1015642

Other (OTH) AF: 0.0000195 AC: 1 AN: 51288

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	13
DANN	Benign	0.94
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.2	L
PhyloP100		-1.1
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	0.050	N
REVEL	Benign	0.021
Sift	Benign	0.23	T
Sift4G	Benign	0.066	T
Polyphen		0.014	B
Vest4		0.19
MutPred		0.26		Gain of MoRF binding (P = 0.0066)
MVP		0.014
MPC		0.064
ClinPred		0.39	T
GERP RS		-0.71
PromoterAI		-0.0064	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.061
gMVP		0.42
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;