13-41719634-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015058.2(VWA8):c.3073A>T(p.Ile1025Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: VWA8 NM_015058.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.92

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4193684).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWA8	NM_015058.2	c.3073A>T	p.Ile1025Leu	missense_variant	26/45	ENST00000379310.8
VWA8	NM_001009814.2	c.3073A>T	p.Ile1025Leu	missense_variant	26/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWA8	ENST00000379310.8	c.3073A>T	p.Ile1025Leu	missense_variant	26/45	2	NM_015058.2	P1
VWA8	ENST00000281496.6	c.3073A>T	p.Ile1025Leu	missense_variant	26/26	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461004 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726818

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2023

The c.3073A>T (p.I1025L) alteration is located in exon 26 (coding exon 26) of the VWA8 gene. This alteration results from a A to T substitution at nucleotide position 3073, causing the isoleucine (I) at amino acid position 1025 to be replaced by a leucine (L). 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	Uncertain	0.37
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.038	T;.
Eigen	Benign	-0.051
Eigen_PC	Benign	0.017
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.42	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.23
Sift	Benign	0.037	D;T
Sift4G	Benign	0.22	T;T
Polyphen		0.52	P;.
Vest4		0.61
MutPred		0.67		Gain of catalytic residue at I1025 (P = 0.0289);Gain of catalytic residue at I1025 (P = 0.0289);
MVP		0.061
MPC		0.10
ClinPred		0.96	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.27
gMVP		0.64

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-42293770;