Genetic Variant VWCE:p.Ser926Pro (chr11-61258767-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_152718.2(VWCE):c.2776T>C(p.Ser926Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000672 in 1,488,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S926F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000067 ( 0 hom. )

Consequence

VWCE
NM_152718.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.271

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]

VWCE links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13573062).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWCE	NM_152718.2 link	c.2776T>C	p.Ser926Pro	missense_variant	Exon 20 of 20	ENST00000335613.10	NP_689931.2	Q96DN2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
VWCE	ENST00000335613.10 link	c.2776T>C	p.Ser926Pro	missense_variant	Exon 20 of 20	1	NM_152718.2	ENSP00000334186.5	Q96DN2-1
VWCE	ENST00000301770.10 link	n.*2173T>C		non_coding_transcript_exon_variant	Exon 20 of 20	1		ENSP00000301770.6	Q96DN2-2
VWCE	ENST00000301770.10 link	n.*2173T>C		3_prime_UTR_variant	Exon 20 of 20	1		ENSP00000301770.6	Q96DN2-2
VWCE	ENST00000535710.1 link	c.1171T>C	p.Ser391Pro	missense_variant	Exon 9 of 9	2		ENSP00000442570.1	B4DY31

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151826

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000592

AC:

AN:

168784

Hom.:

AF XY:

0.00

AC XY:

AN XY:

89096

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000119

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000674

AC:

AN:

1336246

Hom.:

Cov.:

AF XY:

0.0000107

AC XY:

AN XY:

651952

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000855

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151826

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74140

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000881

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2776T>C (p.S926P) alteration is located in exon 20 (coding exon 20) of the VWCE gene. This alteration results from a T to C substitution at nucleotide position 2776, causing the serine (S) at amino acid position 926 to be replaced by a proline (P). 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

0.085

BayesDel_addAF

Benign

-0.023

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.010

T;T;T

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.51

T;T;T

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.14

T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

1.0

.;L;.

PrimateAI

Benign

0.33

PROVEAN

Benign

0.30

.;N;N

REVEL

Benign

0.18

Sift

Uncertain

0.015

.;D;D

Sift4G

Uncertain

0.060

T;T;D

Polyphen

0.86

.;P;.

Vest4

0.14

MutPred

0.13

.;Loss of phosphorylation at S926 (P = 0.028);.;

MVP

0.20

MPC

0.52

ClinPred

0.19

GERP RS

-0.55

Varity_R

0.058

gMVP

0.16

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