chr12-6064267-C-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_000552.5(VWF):​c.1411G>A​(p.Val471Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,614,044 control chromosomes in the GnomAD database, including 11,844 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1091 hom., cov: 33)
Exomes 𝑓: 0.12 ( 10753 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

18

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.00400

Publications

26 publications found
Variant links:
Genes affected
VWF (HGNC:12726): (von Willebrand factor) This gene encodes a glycoprotein involved in hemostasis. The encoded preproprotein is proteolytically processed following assembly into large multimeric complexes. These complexes function in the adhesion of platelets to sites of vascular injury and the transport of various proteins in the blood. Mutations in this gene result in von Willebrand disease, an inherited bleeding disorder. An unprocessed pseudogene has been found on chromosome 22. [provided by RefSeq, Oct 2015]
VWF Gene-Disease associations (from GenCC):
  • hereditary von Willebrand disease
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • von Willebrand disease type 2B
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
  • von Willebrand disease 2
    Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
  • von Willebrand disease 1
    Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
  • von Willebrand disease type 2A
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • von Willebrand disease type 2M
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • von Willebrand disease 3
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • von Willebrand disease type 2N
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP2
Missense variant in the VWF gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 149 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: 0.98969 (below the threshold of 3.09). Trascript score misZ: 3.5064 (above the threshold of 3.09). GenCC associations: The gene is linked to hereditary von Willebrand disease, von Willebrand disease type 2B, von Willebrand disease 1, von Willebrand disease 2, von Willebrand disease type 2A, von Willebrand disease type 2M, von Willebrand disease 3, von Willebrand disease type 2N.
BP4
Computational evidence support a benign effect (MetaRNN=0.0015455186).
BP6
Variant 12-6064267-C-T is Benign according to our data. Variant chr12-6064267-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6064267-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6064267-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6064267-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 256652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
VWFNM_000552.5 linkc.1411G>A p.Val471Ile missense_variant Exon 12 of 52 ENST00000261405.10 NP_000543.3 P04275-1
VWFXM_047429501.1 linkc.1411G>A p.Val471Ile missense_variant Exon 12 of 52 XP_047285457.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
VWFENST00000261405.10 linkc.1411G>A p.Val471Ile missense_variant Exon 12 of 52 1 NM_000552.5 ENSP00000261405.5 P04275-1
VWFENST00000538635.5 linkn.420+46248G>A intron_variant Intron 5 of 5 4

Frequencies

GnomAD3 genomes
AF:
0.116
AC:
17587
AN:
152142
Hom.:
1092
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.139
Gnomad AMI
AF:
0.0537
Gnomad AMR
AF:
0.0625
Gnomad ASJ
AF:
0.0424
Gnomad EAS
AF:
0.168
Gnomad SAS
AF:
0.176
Gnomad FIN
AF:
0.0930
Gnomad MID
AF:
0.0854
Gnomad NFE
AF:
0.114
Gnomad OTH
AF:
0.0918
GnomAD2 exomes
AF:
0.114
AC:
28579
AN:
250654
AF XY:
0.118
show subpopulations
Gnomad AFR exome
AF:
0.137
Gnomad AMR exome
AF:
0.0483
Gnomad ASJ exome
AF:
0.0507
Gnomad EAS exome
AF:
0.171
Gnomad FIN exome
AF:
0.0983
Gnomad NFE exome
AF:
0.115
Gnomad OTH exome
AF:
0.102
GnomAD4 exome
AF:
0.117
AC:
171222
AN:
1461782
Hom.:
10753
Cov.:
33
AF XY:
0.119
AC XY:
86576
AN XY:
727192
show subpopulations
African (AFR)
AF:
0.132
AC:
4431
AN:
33480
American (AMR)
AF:
0.0501
AC:
2242
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.0490
AC:
1281
AN:
26134
East Asian (EAS)
AF:
0.163
AC:
6463
AN:
39698
South Asian (SAS)
AF:
0.175
AC:
15062
AN:
86256
European-Finnish (FIN)
AF:
0.0995
AC:
5306
AN:
53352
Middle Eastern (MID)
AF:
0.0970
AC:
559
AN:
5762
European-Non Finnish (NFE)
AF:
0.116
AC:
128862
AN:
1111980
Other (OTH)
AF:
0.116
AC:
7016
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.470
Heterozygous variant carriers
0
9872
19743
29615
39486
49358
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
4736
9472
14208
18944
23680
<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:
0.116
AC:
17590
AN:
152262
Hom.:
1091
Cov.:
33
AF XY:
0.114
AC XY:
8474
AN XY:
74460
show subpopulations
African (AFR)
AF:
0.139
AC:
5758
AN:
41550
American (AMR)
AF:
0.0623
AC:
953
AN:
15308
Ashkenazi Jewish (ASJ)
AF:
0.0424
AC:
147
AN:
3468
East Asian (EAS)
AF:
0.169
AC:
873
AN:
5168
South Asian (SAS)
AF:
0.176
AC:
849
AN:
4820
European-Finnish (FIN)
AF:
0.0930
AC:
987
AN:
10610
Middle Eastern (MID)
AF:
0.0952
AC:
28
AN:
294
European-Non Finnish (NFE)
AF:
0.114
AC:
7754
AN:
68018
Other (OTH)
AF:
0.0908
AC:
192
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.501
Heterozygous variant carriers
0
819
1638
2458
3277
4096
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
208
416
624
832
1040
<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:
0.114
Hom.:
3360
Bravo
AF:
0.112
TwinsUK
AF:
0.115
AC:
427
ALSPAC
AF:
0.111
AC:
428
ESP6500AA
AF:
0.139
AC:
611
ESP6500EA
AF:
0.110
AC:
948
ExAC
AF:
0.118
AC:
14348
Asia WGS
AF:
0.166
AC:
576
AN:
3478
EpiCase
AF:
0.107
EpiControl
AF:
0.107

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Mar 11, 2020
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Oct 29, 2018
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Benign:1
-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

von Willebrand disease type 2 Benign:1
Dec 05, 2021
Genome-Nilou Lab
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

von Willebrand disease type 3 Benign:1
Dec 05, 2021
Genome-Nilou Lab
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

von Willebrand disease type 1 Benign:1
Dec 05, 2021
Genome-Nilou Lab
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Hereditary von Willebrand disease Benign:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.068
BayesDel_addAF
Benign
-0.70
T
BayesDel_noAF
Benign
-0.63
CADD
Benign
4.2
DANN
Benign
0.40
DEOGEN2
Benign
0.25
T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.097
N
LIST_S2
Benign
0.78
T
MetaRNN
Benign
0.0015
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.055
N
PhyloP100
0.0040
PrimateAI
Benign
0.27
T
PROVEAN
Benign
-0.37
N
REVEL
Benign
0.13
Sift
Benign
0.96
T
Sift4G
Benign
1.0
T
Polyphen
0.019
B
Vest4
0.038
MPC
0.21
ClinPred
0.0031
T
GERP RS
-2.9
Varity_R
0.032
gMVP
0.12
Mutation Taster
=95/5
polymorphism (auto)

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

Other links and lift over

dbSNP: rs1800377; hg19: chr12-6173433; COSMIC: COSV107218037; API