11-61259064-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_152718.2(VWCE):​c.2479G>A​(p.Ala827Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00026 in 1,613,830 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00016 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

VWCE
NM_152718.2 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.725
Variant links:
Genes affected
VWCE (HGNC:26487): (von Willebrand factor C and EGF domains) Predicted to enable calcium ion binding activity. Involved in cellular response to virus. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.029761583).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
VWCENM_152718.2 linkc.2479G>A p.Ala827Thr missense_variant Exon 20 of 20 ENST00000335613.10 NP_689931.2 Q96DN2-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
VWCEENST00000335613.10 linkc.2479G>A p.Ala827Thr missense_variant Exon 20 of 20 1 NM_152718.2 ENSP00000334186.5 Q96DN2-1

Frequencies

GnomAD3 genomes
AF:
0.000164
AC:
25
AN:
152154
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000265
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000191
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000207
AC:
52
AN:
250822
Hom.:
0
AF XY:
0.000184
AC XY:
25
AN XY:
135608
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.000318
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000218
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000291
Gnomad OTH exome
AF:
0.000327
GnomAD4 exome
AF:
0.000270
AC:
395
AN:
1461676
Hom.:
0
Cov.:
31
AF XY:
0.000252
AC XY:
183
AN XY:
727124
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.000246
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000227
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000131
Gnomad4 NFE exome
AF:
0.000319
Gnomad4 OTH exome
AF:
0.000182
GnomAD4 genome
AF:
0.000164
AC:
25
AN:
152154
Hom.:
0
Cov.:
32
AF XY:
0.000148
AC XY:
11
AN XY:
74332
show subpopulations
Gnomad4 AFR
AF:
0.000265
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000191
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000258
Hom.:
0
Bravo
AF:
0.000204
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000778
AC:
3
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.000206
AC:
25
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000382
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Aug 04, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2479G>A (p.A827T) alteration is located in exon 20 (coding exon 20) of the VWCE gene. This alteration results from a G to A substitution at nucleotide position 2479, causing the alanine (A) at amino acid position 827 to be replaced by a threonine (T). 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
0.068
BayesDel_addAF
Benign
-0.53
T
BayesDel_noAF
Benign
-0.69
CADD
Benign
0.053
DANN
Benign
0.57
DEOGEN2
Benign
0.0032
T;T;T
Eigen
Benign
-2.1
Eigen_PC
Benign
-2.1
FATHMM_MKL
Benign
0.015
N
LIST_S2
Benign
0.44
T;T;T
M_CAP
Benign
0.043
D
MetaRNN
Benign
0.030
T;T;T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
-0.69
.;N;.
PrimateAI
Benign
0.28
T
PROVEAN
Benign
-0.20
.;N;N
REVEL
Benign
0.0
Sift
Benign
0.18
.;T;T
Sift4G
Benign
0.66
T;T;T
Polyphen
0.0010
.;B;.
Vest4
0.013
MVP
0.030
MPC
0.20
ClinPred
0.033
T
GERP RS
-8.0
Varity_R
0.029
gMVP
0.12

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.

Other links and lift over

dbSNP: rs141851975; hg19: chr11-61026536; COSMIC: COSV57112293; COSMIC: COSV57112293; API