Genetic Variant VWDE:p.Arg1548Pro (chr7-12336152-C-G) – 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_001135924.3(VWDE):c.4643G>C(p.Arg1548Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000535 in 1,550,652 control chromosomes in the GnomAD database, including 2 homozygotes. 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. R1548L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 1 hom., cov: 33)

Exomes 𝑓: 0.000052 ( 1 hom. )

Consequence

VWDE
NM_001135924.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.727

Publications

1 publications found

Variant links:

Genes affected

VWDE (HGNC:21897): (von Willebrand factor D and EGF domains) Predicted to enable signaling receptor binding activity. Predicted to be involved in anatomical structure development. Predicted to be active in cell surface and extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

VWDE 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=0.040341556).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001135924.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VWDE	NM_001135924.3	MANE Select	c.4643G>C	p.Arg1548Pro	missense	Exon 27 of 29	NP_001129396.1	Q8N2E2-1
VWDE	NM_001346972.2		c.4298G>C	p.Arg1433Pro	missense	Exon 25 of 27	NP_001333901.1
VWDE	NM_001346973.2		c.3833G>C	p.Arg1278Pro	missense	Exon 25 of 27	NP_001333902.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VWDE	ENST00000275358.8	TSL:5 MANE Select	c.4643G>C	p.Arg1548Pro	missense	Exon 27 of 29	ENSP00000275358.3	Q8N2E2-1
VWDE	ENST00000452576.6	TSL:1	n.*1407G>C		non_coding_transcript_exon	Exon 28 of 30	ENSP00000401687.2	J3KQJ9
VWDE	ENST00000452576.6	TSL:1	n.*1407G>C		3_prime_UTR	Exon 28 of 30	ENSP00000401687.2	J3KQJ9

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

152052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000141

AC:

AN:

156390

AF XY:

0.000181

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00

GnomAD4 exome

AF:

0.0000522

AC:

AN:

1398482

Hom.:

Cov.:

AF XY:

0.0000710

AC XY:

AN XY:

689694

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31556

American (AMR)

AF:

0.00

AC:

AN:

35492

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25162

East Asian (EAS)

AF:

0.00

AC:

AN:

35684

South Asian (SAS)

AF:

0.000886

AC:

AN:

78990

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49298

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078634

Other (OTH)

AF:

0.0000517

AC:

AN:

57974

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

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:

0.0000657

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41526

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00208

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00

Hom.:

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.021

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.46

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.64

M_CAP

Benign

0.052

MetaRNN

Benign

0.040

MetaSVM

Benign

-0.94

MutationAssessor

Pathogenic

2.9

PhyloP100

0.73

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.6

REVEL

Benign

0.13

Sift

Benign

0.065

Sift4G

Benign

0.36

Varity_R

0.33

gMVP

0.68

Mutation Taster

=82/18

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over