chr12-5993928-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM1PP2BP4_Moderate

The NM_000552.5(VWF):​c.6532G>A​(p.Ala2178Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. A2178S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

19

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0150

Publications

14 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: Uncertain_significance. The variant received 1 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000552.5
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=0.1548537).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
VWFNM_000552.5 linkc.6532G>A p.Ala2178Thr missense_variant Exon 37 of 52 ENST00000261405.10 NP_000543.3 P04275-1
VWFXM_047429501.1 linkc.6532G>A p.Ala2178Thr missense_variant Exon 37 of 52 XP_047285457.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
VWFENST00000261405.10 linkc.6532G>A p.Ala2178Thr missense_variant Exon 37 of 52 1 NM_000552.5 ENSP00000261405.5 P04275-1
VWFENST00000538635.5 linkn.427G>A non_coding_transcript_exon_variant Exon 6 of 6 4

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152064
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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
GnomAD2 exomes
AF:
0.0000239
AC:
6
AN:
251010
AF XY:
0.0000221
show subpopulations
Gnomad AFR exome
AF:
0.000124
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000547
AC:
8
AN:
1461814
Hom.:
0
Cov.:
32
AF XY:
0.00000688
AC XY:
5
AN XY:
727196
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86256
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53352
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000360
AC:
4
AN:
1112002
Other (OTH)
AF:
0.0000331
AC:
2
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.494
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.00000658
AC:
1
AN:
152064
Hom.:
0
Cov.:
31
AF XY:
0.0000135
AC XY:
1
AN XY:
74262
show subpopulations
African (AFR)
AF:
0.0000242
AC:
1
AN:
41398
American (AMR)
AF:
0.00
AC:
0
AN:
15264
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5186
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4816
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10600
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68014
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
119
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
13
DANN
Benign
0.93
DEOGEN2
Benign
0.23
T
Eigen
Benign
-1.0
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.070
N
LIST_S2
Benign
0.81
T
M_CAP
Benign
0.064
D
MetaRNN
Benign
0.15
T
MetaSVM
Benign
-0.82
T
MutationAssessor
Benign
1.9
L
PhyloP100
-0.015
PrimateAI
Benign
0.33
T
PROVEAN
Benign
0.0
N
REVEL
Benign
0.17
Sift
Benign
0.29
T
Sift4G
Benign
0.28
T
Polyphen
0.099
B
Vest4
0.059
MutPred
0.70
Gain of catalytic residue at A2181 (P = 0);
MVP
0.29
MPC
0.27
ClinPred
0.047
T
GERP RS
-0.72
Varity_R
0.10
gMVP
0.49
Mutation Taster
=84/16
polymorphism

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

Other links and lift over

dbSNP: rs34230288; hg19: chr12-6103094; API