rs11063987

chr12-6019114-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000552.5(VWF):c.4304A>G(p.Asn1435Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00609 in 1,613,798 control chromosomes in the GnomAD database, including 510 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (272 hom., cov: 31)
  • Exomes 𝑓: 0.0034 (238 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.84

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 -17 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
• PP2: Missense variant where missense usually causes diseases, VWF
• BP4: Computational evidence support a benign effect (MetaRNN=0.0026009083).
• BP6: Variant 12-6019114-T-C is Benign according to our data. Variant chr12-6019114-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 310062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWF	NM_000552.5	c.4304A>G	p.Asn1435Ser	missense_variant	28/52	ENST00000261405.10
VWF	XM_047429501.1	c.4304A>G	p.Asn1435Ser	missense_variant	28/52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWF	ENST00000261405.10	c.4304A>G	p.Asn1435Ser	missense_variant	28/52	1	NM_000552.5	P1
VWF	ENST00000538635.5	n.421-25180A>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0316 AC: 4809 AN: 152018 Hom.: 271 Cov.: 31

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.0268

GnomAD3 exomes AF: 0.00818 AC: 2054 AN: 251132 Hom.: 114 AF XY: 0.00611 AC XY: 829 AN XY: 135724

Gnomad AFR exome AF: 0.111

Gnomad AMR exome AF: 0.00463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000485

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00343 AC: 5017 AN: 1461662 Hom.: 238 Cov.: 98 AF XY: 0.00294 AC XY: 2141 AN XY: 727140

Gnomad4 AFR exome AF: 0.116

Gnomad4 AMR exome AF: 0.00539

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000351

Gnomad4 OTH exome AF: 0.00732

GnomAD4 genome AF: 0.0317 AC: 4817 AN: 152136 Hom.: 272 Cov.: 31 AF XY: 0.0308 AC XY: 2290 AN XY: 74378

Gnomad4 AFR AF: 0.109

Gnomad4 AMR AF: 0.0113

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000662

Gnomad4 OTH AF: 0.0265

Alfa AF: 0.00508 Hom.: 40

Bravo AF: 0.0353

ESP6500AA AF: 0.103 AC: 454

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00988 AC: 1199

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000889

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 12, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 24, 2022	- -

von Willebrand disease type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

von Willebrand disease type 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

von Willebrand disease type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Hereditary von Willebrand disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.10
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.82	N
REVEL	Uncertain	0.60
Sift	Benign	0.19	T
Sift4G	Benign	0.13	T
Polyphen		0.99	D
Vest4		0.15
MVP		0.91
MPC		0.62
ClinPred		0.013	T
GERP RS		4.3
Varity_R		0.14
gMVP		0.58

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: rs11063987; hg19: chr12-6128280;