chr12-6019550-C-T

Position:

• chr12-6019550-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1 PP2 BP4_Strong BS2_Supporting

The NM_000552.5(VWF):​c.3868G>A​(p.Glu1290Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.98

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_benign. Variant got -2 ACMG points.

• PM1: In a helix (size 15) in uniprot entity VWF_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) 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=0.03959188).
• BS2: High AC in GnomAd4 at 89 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5	c.3868G>A	p.Glu1290Lys	missense_variant	28/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.3868G>A	p.Glu1290Lys	missense_variant	28/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.3868G>A	p.Glu1290Lys	missense_variant	28/52	1	NM_000552.5	ENSP00000261405	P1
VWF	ENST00000539641.1	n.666G>A		non_coding_transcript_exon_variant	3/3	3
VWF	ENST00000538635.5	n.421-25616G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.000585 AC: 89 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00205

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000478

GnomAD3 exomes AF: 0.000207 AC: 52 AN: 251084 Hom.: 0 AF XY: 0.000228 AC XY: 31 AN XY: 135714

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000650 AC: 95 AN: 1461666 Hom.: 0 Cov.: 38 AF XY: 0.0000564 AC XY: 41 AN XY: 727142

Gnomad4 AFR exome AF: 0.00248

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000584 AC: 89 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.000644 AC XY: 48 AN XY: 74482

Gnomad4 AFR AF: 0.00205

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000260 Hom.: 0

Bravo AF: 0.000722

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000264 AC: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 15, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 07, 2019	The VWF c.3868G>A; p.Glu1290Lys variant (rs138900040), to our knowledge, is not reported in the medical literature or gene-specific databases in association with von Willebrand disease. This variant is found in the African population with an overall allele frequency of 0.25% (63/24954 alleles) in the Genome Aggregation Database. The glutamate at codon 1290 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious, although a modeling study incorporating population data and VWF levels suggested the p.Glu1290Lys variant had a low probability of being disease-causing (Cheng 2016). However, given the lack of clinical and functional data, the significance of the p.Glu1290Lys variant is uncertain at this time. References: Cheng Y et al. Group association test using a hidden Markov model. Biostatistics. 2016 Apr;17(2):221-34. -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The VWF p.Glu1290Lys variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs138900040) and in ClinVar (classified as a VUS by Quest Diagnostics Nichols Institute San Juan Capistrano). The variant was also identified in control databases in 71 of 282484 chromosomes at a frequency of 0.000251 (Genome Aggregation Database Feb 27, 2017) and was observed in the following populations: African in 63 of 24954 chromosomes (freq: 0.002525), Latino in 5 of 35440 chromosomes (freq: 0.000141), South Asian in 2 of 30616 chromosomes (freq: 0.000065) and European (non-Finnish) in 1 of 128814 chromosomes (freq: 0.000008), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), and Other populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Glu1290 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Benign	0.040	T
MetaSVM	Uncertain	0.55	D
MutationAssessor	Pathogenic	3.2	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.4	N
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.48
MVP		0.82
MPC		0.79
ClinPred		0.16	T
GERP RS		3.3
Varity_R		0.45
gMVP		0.93

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: rs138900040; hg19: chr12-6128716;