rs34230288

chr12-5993928-C-Achr12-5993928-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 3P and 13B. PM1 PP2 BP4_Strong BP6 BS1 BS2

The NM_000552.5(VWF):c.6532G>T(p.Ala2178Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,613,996 control chromosomes in the GnomAD database, including 339 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2178V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (14 hom., cov: 31)
  • Exomes 𝑓: 0.019 (325 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.0150

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 -10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000552.5
• PP2: Missense variant where missense usually causes diseases, VWF
• BP4: Computational evidence support a benign effect (MetaRNN=0.008763671).
• BP6: Variant 12-5993928-C-A is Benign according to our data. Variant chr12-5993928-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 619942.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=1, Uncertain_significance=1}. Variant chr12-5993928-C-A is described in Lovd as [Benign]. Variant chr12-5993928-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0125 (1896/152182) while in subpopulation NFE AF= 0.0215 (1462/68006). AF 95% confidence interval is 0.0206. There are 14 homozygotes in gnomad4. There are 848 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1897 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWF	NM_000552.5	c.6532G>T	p.Ala2178Ser	missense_variant	37/52	ENST00000261405.10
VWF	XM_047429501.1	c.6532G>T	p.Ala2178Ser	missense_variant	37/52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWF	ENST00000261405.10	c.6532G>T	p.Ala2178Ser	missense_variant	37/52	1	NM_000552.5	P1
VWF	ENST00000538635.5	n.427G>T		non_coding_transcript_exon_variant	6/6	4

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1897 AN: 152064 Hom.: 14 Cov.: 31

Gnomad AFR AF: 0.00403

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.00819

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00395

Gnomad FIN AF: 0.00726

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0215

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.0113 AC: 2825 AN: 251010 Hom.: 31 AF XY: 0.0112 AC XY: 1525 AN XY: 135710

Gnomad AFR exome AF: 0.00284

Gnomad AMR exome AF: 0.00454

Gnomad ASJ exome AF: 0.00388

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00255

Gnomad FIN exome AF: 0.00899

Gnomad NFE exome AF: 0.0197

Gnomad OTH exome AF: 0.0119

GnomAD4 exome AF: 0.0192 AC: 28029 AN: 1461814 Hom.: 325 Cov.: 32 AF XY: 0.0185 AC XY: 13463 AN XY: 727196

Gnomad4 AFR exome AF: 0.00329

Gnomad4 AMR exome AF: 0.00454

Gnomad4 ASJ exome AF: 0.00448

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00255

Gnomad4 FIN exome AF: 0.00928

Gnomad4 NFE exome AF: 0.0233

Gnomad4 OTH exome AF: 0.0161

GnomAD4 genome AF: 0.0125 AC: 1896 AN: 152182 Hom.: 14 Cov.: 31 AF XY: 0.0114 AC XY: 848 AN XY: 74390

Gnomad4 AFR AF: 0.00402

Gnomad4 AMR AF: 0.00818

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00395

Gnomad4 FIN AF: 0.00726

Gnomad4 NFE AF: 0.0215

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.0174 Hom.: 60

Bravo AF: 0.0118

TwinsUK AF: 0.0194 AC: 72

ALSPAC AF: 0.0234 AC: 90

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.0226 AC: 194

ExAC AF: 0.0113 AC: 1372

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0197

EpiControl AF: 0.0167

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	VWF: BP4, BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 03, 2023	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 29, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	4.6
Dann	Benign	0.80
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.47	N
REVEL	Benign	0.12
Sift	Benign	0.58	T
Sift4G	Benign	0.91	T
Polyphen		0.0020	B
Vest4		0.081
MPC		0.25
ClinPred		0.00058	T
GERP RS		-0.72
Varity_R		0.067
gMVP		0.37

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: rs34230288; hg19: chr12-6103094; COSMIC: COSV99075171;