Genetic Variant VWA3B:p.Lys622Arg (chr2-98217874-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM2PM5BP4_Strong

The NM_144992.5(VWA3B):c.1865A>G(p.Lys622Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K622T) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

VWA3B
NM_144992.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.07

Publications

3 publications found

Variant links:

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]

VWA3B Gene-Disease associations (from GenCC):

spinocerebellar ataxia, autosomal recessive 22
Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

VWA3B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-98217874-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 226428.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.06056279).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWA3B	NM_144992.5 link	c.1865A>G	p.Lys622Arg	missense_variant	Exon 14 of 28	ENST00000477737.6	NP_659429.4	Q502W6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWA3B	ENST00000477737.6 link	c.1865A>G	p.Lys622Arg	missense_variant	Exon 14 of 28	1	NM_144992.5	ENSP00000417955.1		Q502W6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458058

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725360

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33218

American (AMR)

AF:

0.00

AC:

AN:

44362

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25996

East Asian (EAS)

AF:

0.00

AC:

AN:

39394

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85780

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110722

Other (OTH)

AF:

0.00

AC:

AN:

60240

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

CADD

Benign

6.8

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.0011

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.57

M_CAP

Benign

0.0028

MetaRNN

Benign

0.061

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.95

PhyloP100

1.1

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.80

REVEL

Benign

0.011

Sift

Benign

0.24

Sift4G

Benign

0.49

Polyphen

0.034

Vest4

0.093

MutPred

0.43

Loss of methylation at K622 (P = 0.007);

MVP

0.076

MPC

0.073

ClinPred

0.067

GERP RS

2.1

Varity_R

0.061

gMVP

0.25

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over