Genetic Variant VWA8:p.Pro11Ser (chr13-41960985-G-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting

The NM_015058.2(VWA8):c.31C>T(p.Pro11Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000557 in 1,257,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000056 ( 0 hom. )

Consequence

VWA8
NM_015058.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.22

Variant links:

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 links:

VWA8-AS1 (HGNC:44270): (VWA8 antisense RNA 1 (head to head))

VWA8-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17008173).

BS2

High AC in GnomAdExome4 at 7 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWA8	NM_015058.2 link	c.31C>T	p.Pro11Ser	missense_variant	Exon 1 of 45	ENST00000379310.8	NP_055873.1	A3KMH1-1
VWA8	NM_001009814.2 link	c.31C>T	p.Pro11Ser	missense_variant	Exon 1 of 26		NP_001009814.1	A3KMH1-2
VWA8-AS1	NR_039974.1 link	n.-184G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
VWA8	ENST00000379310.8 link	c.31C>T	p.Pro11Ser	missense_variant	Exon 1 of 45	2	NM_015058.2	ENSP00000368612.3	A3KMH1-1
VWA8	ENST00000281496.6 link	c.31C>T	p.Pro11Ser	missense_variant	Exon 1 of 26	1		ENSP00000281496.6	A3KMH1-2
VWA8-AS1	ENST00000612345.4 link	n.71+5107G>A		intron_variant	Intron 1 of 3	2
VWA8-AS1	ENST00000611103.1 link	n.-184G>A		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000417

AC:

AN:

23968

Hom.:

AF XY:

0.0000712

AC XY:

AN XY:

14038

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000109

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000557

AC:

AN:

1257468

Hom.:

Cov.:

AF XY:

0.00000652

AC XY:

AN XY:

613930

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000684

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.31C>T (p.P11S) alteration is located in exon 1 (coding exon 1) of the VWA8 gene. This alteration results from a C to T substitution at nucleotide position 31, causing the proline (P) at amino acid position 11 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.018

T;.

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.69

T;T

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.55

N;N

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.78

N;N

REVEL

Benign

0.022

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

0.074

T;T

Polyphen

0.011

B;.

Vest4

0.33

MutPred

0.19

Gain of MoRF binding (P = 0.0294);Gain of MoRF binding (P = 0.0294);

MVP

0.072

MPC

0.056

ClinPred

0.23

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.10

gMVP

0.29

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over