3-184230604-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001390846.1(VWA5B2):c.76G>A(p.Gly26Ser) variant causes a missense change. 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: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: VWA5B2 NM_001390846.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.84

Genes affected

VWA5B2 (HGNC:25144): (von Willebrand factor A domain containing 5B2)

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.804

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWA5B2	NM_001390846.1	c.76G>A	p.Gly26Ser	missense_variant	2/20	ENST00000691901.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWA5B2	ENST00000691901.1	c.76G>A	p.Gly26Ser	missense_variant	2/20		NM_001390846.1	P1
VWA5B2	ENST00000426955.6	c.76G>A	p.Gly26Ser	missense_variant	1/19	1		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1293344 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 637416

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000264

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 07, 2022

The c.76G>A (p.G26S) alteration is located in exon 1 (coding exon 1) of the VWA5B2 gene. This alteration results from a G to A substitution at nucleotide position 76, causing the glycine (G) at amino acid position 26 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	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Benign	0.026	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.53
MutPred		0.70		Loss of catalytic residue at G26 (P = 0.02);
MVP		0.35
MPC		1.6
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.81
gMVP		0.75

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

Other links and lift over

dbSNP: rs1387193581; hg19: chr3-183948392;