chr12-6019171-A-G

Position:

• chr12-6019171-A-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PP2 PP3_Moderate PP5_Very_Strong

The NM_000552.5(VWF):​c.4247T>C​(p.Ile1416Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.60

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]

VWF (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a disulfide_bond (size 186) in uniprot entity VWF_HUMAN there are 58 pathogenic changes around while only 4 benign (94%) 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922
• PP5: Variant 12-6019171-A-G is Pathogenic according to our data. Variant chr12-6019171-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 439338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5	c.4247T>C	p.Ile1416Thr	missense_variant	28/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.4247T>C	p.Ile1416Thr	missense_variant	28/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.4247T>C	p.Ile1416Thr	missense_variant	28/52	1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000538635.5	n.421-25237T>C		intron_variant		4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251152 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135736

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461672 Hom.: 0 Cov.: 99 AF XY: 0.00000413 AC XY: 3 AN XY: 727146

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: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 29, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 16, 2024	PP1_strong, PP5, PM2, PS3, PS4_moderate -

Hereditary von Willebrand disease Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 14, 2022	Variant summary: VWF c.4247T>C (p.Ile1416Thr) results in a non-conservative amino acid change located in the type A1 domain (IPR002035), affecting the binding site for platelet glycoprotein Ib (amino acids 1277 -1453; UniProt) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251152 control chromosomes (gnomAD). c.4247T>C has been reported in the literature in multiple individuals in a family, who were affected with Von Willebrand Disease (McKinnon_2012). These data indicate that the variant is very likely to be associated with disease. This publication also reported experimental evidence evaluating an impact on protein function, and demonstrated significantly reduced glycoprotein Ib binding (McKinnon_2012). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 , and both of them classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 02, 2020	The VWF c.4247T>C (p.Ile1416Thr) variant is a missense variant that has been reported in two studies, in which it is found in a heterozygous state in 11 individuals from two families with von Willebrand disease type 2 (McKinnon et al. 2012; Starke et al. 2013). The large family reported in McKinnon et al. (2012) includes nine affected individuals across three generations. The p.Ile1416Thr variant was absent from nine control subjects. It is reported at a frequency of 0.000009 in the European (non-Finnish) population of the Genome Aggregation Database though this is based on one allele in a region of good sequence coverage so the variant is presumed to be rare. The variant is in the A1 domain of the protein, and transient transfection in HEK293T cells reduced expression by ~40% and significantly reduced GPIb-a (McKinnon et al. 2012). Another pathogenic variant, p.Ile1416Asn, is located at the same amino acid residue (McKinnon et al. 2012). Based on the collective evidence and application of the ACMG criteria, the p.Ile1416Thr variant is classified as pathogenic for von Willebrand disease. -

von Willebrand disease type 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Jul 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.5	M
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.24	N
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.53		Gain of catalytic residue at G1417 (P = 0);
MVP		0.88
MPC		1.1
ClinPred		0.94	D
GERP RS		4.9
Varity_R		0.36
gMVP		0.80

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: rs61750081; hg19: chr12-6128337;