11-61258971-G-A

Position:

• chr11-61258971-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000335613.10(VWCE):​c.2572C>T​(p.Pro858Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000347 in 1,442,644 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: VWCE ENST00000335613.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.51

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWCE	NM_152718.2	c.2572C>T	p.Pro858Ser	missense_variant	20/20	ENST00000335613.10	NP_689931.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWCE	ENST00000335613.10	c.2572C>T	p.Pro858Ser	missense_variant	20/20	1	NM_152718.2	ENSP00000334186.5
VWCE	ENST00000301770.10	n.*1969C>T		non_coding_transcript_exon_variant	20/20	1		ENSP00000301770.6
VWCE	ENST00000301770.10	n.*1969C>T		3_prime_UTR_variant	20/20	1		ENSP00000301770.6
VWCE	ENST00000535710.1	c.967C>T	p.Pro323Ser	missense_variant	9/9	2		ENSP00000442570.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000347 AC: 5 AN: 1442644 Hom.: 0 Cov.: 31 AF XY: 0.00000279 AC XY: 2 AN XY: 716112

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: 0.00000453

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 30, 2024

The c.2572C>T (p.P858S) alteration is located in exon 20 (coding exon 20) of the VWCE gene. This alteration results from a C to T substitution at nucleotide position 2572, causing the proline (P) at amino acid position 858 to be replaced by a serine (S). 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	0.088
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.049	T;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.65	T;T
M_CAP	Pathogenic	0.68	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	0.53	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.5	N;D
REVEL	Benign	0.088
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.87	P;.
Vest4		0.28
MutPred		0.27		Gain of phosphorylation at P858 (P = 0.0131);.;
MVP		0.72
MPC		0.48
ClinPred		0.89	D
GERP RS		4.6
Varity_R		0.11
gMVP		0.41

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

Other links and lift over

dbSNP: rs1379000675; hg19: chr11-61026443;