NM_022834.5:c.161G>C

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_022834.5(VWA1):c.161G>C(p.Arg54Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,612,336 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

VWA1
NM_022834.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 1.64

Variant links:

Genes affected

VWA1 (HGNC:30910): (von Willebrand factor A domain containing 1) VWA1 belongs to the von Willebrand factor (VWF; MIM 613160) A (VWFA) domain superfamily of extracellular matrix proteins and appears to play a role in cartilage structure and function (Fitzgerald et al., 2002 [PubMed 12062410]).[supplied by OMIM, Nov 2010]

VWA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-1437014-G-C is Pathogenic according to our data. Variant chr1-1437014-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3237466.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWA1	NM_022834.5 link	c.161G>C	p.Arg54Pro	missense_variant	Exon 2 of 3	ENST00000476993.2	NP_073745.2	Q6PCB0-1
VWA1	NM_199121.3 link	c.74-308G>C		intron_variant	Intron 1 of 2		NP_954572.2	Q6PCB0-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
VWA1	ENST00000476993.2 link	c.161G>C	p.Arg54Pro	missense_variant	Exon 2 of 3	1	NM_022834.5	ENSP00000417185.1	Q6PCB0-1
VWA1	ENST00000495558.1 link	c.56G>C	p.Arg19Pro	missense_variant	Exon 2 of 2	2		ENSP00000463643.1	J3QLP3
VWA1	ENST00000471398.1 link	c.281G>C	p.Arg94Pro	missense_variant	Exon 2 of 2	3		ENSP00000464343.1	J3QRR0
VWA1	ENST00000338660.5 link	c.74-308G>C		intron_variant	Intron 1 of 2	2		ENSP00000423404.1	Q6PCB0-3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000105

AC:

AN:

247770

Hom.:

AF XY:

0.0000817

AC XY:

AN XY:

134684

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000725

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1460120

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

726316

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000717

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

AF:

0.0000131

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000831

ExAC

AF:

0.0000495

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Neuronopathy, distal hereditary motor, autosomal recessive 7

Pathogenic:1

Feb 05, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1

Jul 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.161G>C (p.R54P) alteration is located in exon 2 (coding exon 2) of the VWA1 gene. This alteration results from a G to C substitution at nucleotide position 161, causing the arginine (R) at amino acid position 54 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Sep 16, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Benign

-0.072

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

DANN

Benign

0.79

DEOGEN2

Pathogenic

0.83

.;D;.

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Benign

0.61

LIST_S2

Uncertain

0.87

D;D;T

M_CAP

Pathogenic

0.33

MetaRNN

Uncertain

0.58

D;D;D

MetaSVM

Uncertain

0.13

MutationAssessor

Pathogenic

3.0

.;M;.

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-4.7

.;D;.

REVEL

Uncertain

0.64

Sift

Uncertain

0.013

.;D;.

Sift4G

Uncertain

0.015

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.70

MutPred

0.70

.;Gain of catalytic residue at R54 (P = 0.0367);.;

MVP

0.84

MPC

0.28

ClinPred

0.40

GERP RS

0.34

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.78

gMVP

0.90

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over