rs1800382

chr12-6019222-C-Achr12-6019222-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate

The NM_000552.5(VWF):c.4196G>T(p.Arg1399Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1399C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.26

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a disulfide_bond (size 186) in uniprot entity VWF_HUMAN there are 108 pathogenic changes around while only 5 benign (96%) in NM_000552.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-6019223-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 100337.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=7, not_provided=1, Uncertain_significance=1}.
• PP2: Missense variant where missense usually causes diseases, VWF
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWF	NM_000552.5	c.4196G>T	p.Arg1399Leu	missense_variant	28/52	ENST00000261405.10
VWF	XM_047429501.1	c.4196G>T	p.Arg1399Leu	missense_variant	28/52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWF	ENST00000261405.10	c.4196G>T	p.Arg1399Leu	missense_variant	28/52	1	NM_000552.5	P1
VWF	ENST00000538635.5	n.421-25288G>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250796 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135602

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: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461654 Hom.: 0 Cov.: 98 AF XY: 0.00000138 AC XY: 1 AN XY: 727138

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Pathogenic	3.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.3	N
REVEL	Pathogenic	0.71
Sift	Benign	0.14	T
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.69		Loss of MoRF binding (P = 0.0096);
MVP		0.87
MPC		0.93
ClinPred		0.88	D
GERP RS		4.0
Varity_R		0.35
gMVP		0.83

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: rs1800382; hg19: chr12-6128388;