rs148591481

chr12-6058016-C-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_000552.5(VWF):c.1562G>C(p.Cys521Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0002 in 1,613,320 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Synonymous variant affecting the same amino acid position (i.e. C521C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.36

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PP2: Missense variant where missense usually causes diseases, VWF
• BP4: Computational evidence support a benign effect (MetaRNN=0.04735315).
• BS2: High AC in GnomAd at 163 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWF	NM_000552.5	c.1562G>C	p.Cys521Ser	missense_variant	14/52	ENST00000261405.10
VWF	XM_047429501.1	c.1562G>C	p.Cys521Ser	missense_variant	14/52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWF	ENST00000261405.10	c.1562G>C	p.Cys521Ser	missense_variant	14/52	1	NM_000552.5	P1
VWF	ENST00000538635.5	n.420+52499G>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00107 AC: 163 AN: 152238 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00376

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000305 AC: 76 AN: 248950 Hom.: 0 AF XY: 0.000288 AC XY: 39 AN XY: 135238

Gnomad AFR exome AF: 0.00452

Gnomad AMR exome AF: 0.000116

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: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000110 AC: 160 AN: 1460964 Hom.: 1 Cov.: 32 AF XY: 0.0000922 AC XY: 67 AN XY: 726798

Gnomad4 AFR exome AF: 0.00442

Gnomad4 AMR exome AF: 0.0000671

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: 0.00

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.00107 AC: 163 AN: 152356 Hom.: 0 Cov.: 31 AF XY: 0.000980 AC XY: 73 AN XY: 74492

Gnomad4 AFR AF: 0.00377

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000263 Hom.: 0

Bravo AF: 0.00119

ExAC AF: 0.000404 AC: 49

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

May 10, 2017

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2024

The c.1562G>C (p.C521S) alteration is located in exon 14 (coding exon 13) of the VWF gene. This alteration results from a G to C substitution at nucleotide position 1562, causing the cysteine (C) at amino acid position 521 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	Pathogenic	0.68
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Pathogenic	0.21
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-8.7	D
REVEL	Uncertain	0.50
Sift	Benign	0.063	T
Sift4G	Benign	0.094	T
Polyphen		0.89	P
Vest4		0.93
MutPred		0.67		Gain of catalytic residue at Y516 (P = 0);
MVP		0.92
MPC		0.81
ClinPred		0.12	T
GERP RS		5.0
Varity_R		0.62
gMVP		0.94

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: rs148591481; hg19: chr12-6167182;