3-184234632-G-C

Position:

• chr3-184234632-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001390846.1(VWA5B2):​c.822G>C​(p.Glu274Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: VWA5B2 NM_001390846.1 missense, splice_region
• Scores: Splicing: ADA: 0.3952
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.853

Genes affected

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

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22105283).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWA5B2	NM_001390846.1	c.822G>C	p.Glu274Asp	missense_variant, splice_region_variant	7/20	ENST00000691901.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWA5B2	ENST00000691901.1	c.822G>C	p.Glu274Asp	missense_variant, splice_region_variant	7/20		NM_001390846.1	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

Feb 15, 2023

The c.822G>C (p.E274D) alteration is located in exon 6 (coding exon 6) of the VWA5B2 gene. This alteration results from a G to C substitution at nucleotide position 822, causing the glutamic acid (E) at amino acid position 274 to be replaced by an aspartic acid (D). 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	0.53
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.067	.;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.83	T;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Benign	0.089
Sift	Benign	0.044	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	.;D
Vest4		0.37
MutPred		0.16		.;Loss of sheet (P = 0.007);
MVP		0.13
MPC		1.5
ClinPred		0.94	D
GERP RS		4.0
Varity_R		0.17
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.40
dbscSNV1_RF	Benign	0.47
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: chr3-183952420; COSMIC: COSV56612347; COSMIC: COSV56612347;