12-6034818-T-C

Position:

• chr12-6034818-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 3P and 13B. PM1 PP2 BP4_Strong BP6 BA1

The NM_000552.5(VWF):​c.2555A>G​(p.Gln852Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.906 in 1,614,050 control chromosomes in the GnomAD database, including 662,737 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 Lovd as Benign (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. Q852E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.92 (64098 hom., cov: 33)
  • Exomes 𝑓: 0.90 (598639 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.552

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 in gene, where missense usually causes diseases (based on misZ statistic), VWF. . Gene score misZ 0.98969 (greater than the threshold 3.09). Trascript score misZ 3.5064 (greater than threshold 3.09). GenCC has associacion of gene with von Willebrand disease type 2M, hereditary von Willebrand disease, von Willebrand disease type 2B, von Willebrand disease type 2N, von Willebrand disease 2, von Willebrand disease type 2A, von Willebrand disease 3, von Willebrand disease 1.
• BP4: Computational evidence support a benign effect (MetaRNN=5.94502E-7).
• BP6: Variant 12-6034818-T-C is Benign according to our data. Variant chr12-6034818-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.943 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWF	NM_000552.5	c.2555A>G	p.Gln852Arg	missense_variant	20/52	ENST00000261405.10
VWF	XM_047429501.1	c.2555A>G	p.Gln852Arg	missense_variant	20/52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWF	ENST00000261405.10	c.2555A>G	p.Gln852Arg	missense_variant	20/52	1	NM_000552.5	P1
VWF	ENST00000538635.5	n.421-40884A>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.917 AC: 139460 AN: 152158 Hom.: 64045 Cov.: 33

Gnomad AFR AF: 0.951

Gnomad AMI AF: 0.923

Gnomad AMR AF: 0.922

Gnomad ASJ AF: 0.941

Gnomad EAS AF: 0.792

Gnomad SAS AF: 0.876

Gnomad FIN AF: 0.897

Gnomad MID AF: 0.917

Gnomad NFE AF: 0.908

Gnomad OTH AF: 0.924

GnomAD3 exomes AF: 0.900 AC: 226185 AN: 251332 Hom.: 101983 AF XY: 0.898 AC XY: 121961 AN XY: 135826

Gnomad AFR exome AF: 0.951

Gnomad AMR exome AF: 0.917

Gnomad ASJ exome AF: 0.945

Gnomad EAS exome AF: 0.794

Gnomad SAS exome AF: 0.875

Gnomad FIN exome AF: 0.895

Gnomad NFE exome AF: 0.908

Gnomad OTH exome AF: 0.909

GnomAD4 exome AF: 0.905 AC: 1322288 AN: 1461774 Hom.: 598639 Cov.: 69 AF XY: 0.903 AC XY: 656815 AN XY: 727168

Gnomad4 AFR exome AF: 0.954

Gnomad4 AMR exome AF: 0.916

Gnomad4 ASJ exome AF: 0.945

Gnomad4 EAS exome AF: 0.795

Gnomad4 SAS exome AF: 0.869

Gnomad4 FIN exome AF: 0.888

Gnomad4 NFE exome AF: 0.909

Gnomad4 OTH exome AF: 0.908

GnomAD4 genome AF: 0.917 AC: 139570 AN: 152276 Hom.: 64098 Cov.: 33 AF XY: 0.915 AC XY: 68148 AN XY: 74446

Gnomad4 AFR AF: 0.951

Gnomad4 AMR AF: 0.922

Gnomad4 ASJ AF: 0.941

Gnomad4 EAS AF: 0.792

Gnomad4 SAS AF: 0.877

Gnomad4 FIN AF: 0.897

Gnomad4 NFE AF: 0.908

Gnomad4 OTH AF: 0.919

Alfa AF: 0.911 Hom.: 155696

Bravo AF: 0.921

ESP6500AA AF: 0.950 AC: 4184

ESP6500EA AF: 0.911 AC: 7832

ExAC AF: 0.899 AC: 109150

Asia WGS AF: 0.840 AC: 2924 AN: 3478

EpiCase AF: 0.914

EpiControl AF: 0.918

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	3.9
DANN	Benign	0.54
DEOGEN2	Benign	0.30	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.010	T
MetaRNN	Benign	5.9e-7	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.42	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.086
Sift	Benign	1.0	T
Sift4G	Benign	0.90	T
Polyphen		0.0	B
Vest4		0.037
MPC		0.20
ClinPred		0.00065	T
GERP RS		0.42
Varity_R		0.045
gMVP		0.38

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: rs216321; hg19: chr12-6143984; COSMIC: COSV54629324;