dbSNP rs184297786: VWA5B1:p.Gly180Asp (chr1-20314568-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001039500.3(VWA5B1):c.539G>A(p.Gly180Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000098 in 1,551,586 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000096 ( 0 hom. )

Consequence

VWA5B1
NM_001039500.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.456

Publications

1 publications found

Variant links:

Genes affected

VWA5B1 (HGNC:26538): (von Willebrand factor A domain containing 5B1) Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

VWA5B1 links:

ENSG00000226664 (HGNC:41146):

ENSG00000226664 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011962175).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWA5B1	NM_001039500.3 link	c.539G>A	p.Gly180Asp	missense_variant	Exon 4 of 22	ENST00000289815.13	NP_001034589.2	Q5TIE3-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWA5B1	ENST00000289815.13 link	c.539G>A	p.Gly180Asp	missense_variant	Exon 4 of 22	5	NM_001039500.3	ENSP00000289815.9		Q5TIE3-2

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000689

AC:

107

AN:

155360

AF XY:

0.000570

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00430

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000227

GnomAD4 exome

AF:

0.0000958

AC:

134

AN:

1399338

Hom.:

Cov.:

AF XY:

0.0000913

AC XY:

AN XY:

690178

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31598

American (AMR)

AF:

0.00339

AC:

121

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25180

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.000101

AC:

AN:

79236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49136

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1079000

Other (OTH)

AF:

0.0000861

AC:

AN:

58046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000118

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41550

American (AMR)

AF:

0.00111

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68006

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000102

Hom.:

Bravo

AF:

0.000348

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 17, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.539G>A (p.G180D) alteration is located in exon 4 (coding exon 3) of the VWA5B1 gene. This alteration results from a G to A substitution at nucleotide position 539, causing the glycine (G) at amino acid position 180 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

Benign

0.067

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.74

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0012

T;.

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.56

T;T

M_CAP

Benign

0.0044

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.72

N;N

PhyloP100

0.46

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.5

N;N

REVEL

Benign

0.017

Sift

Benign

0.70

T;T

Sift4G

Benign

0.16

T;T

Polyphen

0.0070

B;B

Vest4

0.12

MVP

0.014

ClinPred

0.037

GERP RS

2.7

Varity_R

0.046

gMVP

0.38

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over