chr2-98119624-G-A

Position:

• chr2-98119624-G-A

Variant summary

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

The NM_144992.5(VWA3B):​c.403G>A​(p.Gly135Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: VWA3B NM_144992.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.27

Genes affected

VWA3B (HGNC:28385): (von Willebrand factor A domain containing 3B) This gene encodes an intracellular protein that contains a von Willebrand factor type A domain. Intracellular proteins with VWA domains are thought to function in transcription, DNA repair, ribosomal and membrane transport and the proteasome. Mutations in this gene are associated with Spinocerebellar ataxia, autosomal recessive 22. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, May 2017]

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, 0.861

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWA3B	NM_144992.5	c.403G>A	p.Gly135Ser	missense_variant	4/28	ENST00000477737.6	NP_659429.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWA3B	ENST00000477737.6	c.403G>A	p.Gly135Ser	missense_variant	4/28	1	NM_144992.5	ENSP00000417955.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

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: 8.99e-7

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

Apr 09, 2024

The c.403G>A (p.G135S) alteration is located in exon 4 (coding exon 3) of the VWA3B gene. This alteration results from a G to A substitution at nucleotide position 403, causing the glycine (G) at amino acid position 135 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	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.50	T
MutationAssessor	Pathogenic	3.1	M
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.67		Gain of catalytic residue at G135 (P = 0.0145);
MVP		0.61
MPC		0.46
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.85
gMVP		0.73

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: chr2-98736087;