13-41721557-T-A

Position:

• chr13-41721557-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_015058.2(VWA8):​c.2777A>T​(p.His926Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VWA8 NM_015058.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.99

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.876

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWA8	NM_015058.2	c.2777A>T	p.His926Leu	missense_variant	25/45	ENST00000379310.8
VWA8	NM_001009814.2	c.2777A>T	p.His926Leu	missense_variant	25/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWA8	ENST00000379310.8	c.2777A>T	p.His926Leu	missense_variant	25/45	2	NM_015058.2	P1
VWA8	ENST00000281496.6	c.2777A>T	p.His926Leu	missense_variant	25/26	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Nov 18, 2023

The c.2777A>T (p.H926L) alteration is located in exon 25 (coding exon 25) of the VWA8 gene. This alteration results from a A to T substitution at nucleotide position 2777, causing the histidine (H) at amino acid position 926 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	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	26
DANN	Benign	0.97
DEOGEN2	Benign	0.36	T;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.9	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-10	D;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.010	D;T
Polyphen		1.0	D;.
Vest4		0.94
MutPred		0.59		Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP		0.32
MPC		0.35
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.84
gMVP		0.91

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: chr13-42295693;