12-5996221-G-A

Variant names:

• chr12-5996221-G-A
• rs216902
• NM_000552.5:c.5844C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000552.5(VWF):​c.5844C>T​(p.Cys1948Cys) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.399 in 1,607,762 control chromosomes in the GnomAD database, including 133,660 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11845 hom., cov: 32)
  • Exomes 𝑓: 0.40 (121815 hom.)
• Consequence: VWF NM_000552.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.00001009
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.04
• Publications: 24 publications found

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 Gene-Disease associations (from GenCC):

• hereditary von Willebrand disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• von Willebrand disease type 2B

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• von Willebrand disease 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• von Willebrand disease 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• von Willebrand disease type 2A

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• von Willebrand disease type 2M

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• von Willebrand disease 3

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• von Willebrand disease type 2N

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 12-5996221-G-A is Benign according to our data. Variant chr12-5996221-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.726 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000552.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	NM_000552.5	MANE Select	c.5844C>T	p.Cys1948Cys	splice_region synonymous	Exon 35 of 52	NP_000543.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	ENST00000261405.10	TSL:1 MANE Select	c.5844C>T	p.Cys1948Cys	splice_region synonymous	Exon 35 of 52	ENSP00000261405.5
	VWF	ENST00000538635.5	TSL:4	n.421-2287C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.384 AC: 58298 AN: 151844 Hom.: 11821 Cov.: 32

Gnomad AFR AF: 0.312

Gnomad AMI AF: 0.413

Gnomad AMR AF: 0.446

Gnomad ASJ AF: 0.343

Gnomad EAS AF: 0.744

Gnomad SAS AF: 0.525

Gnomad FIN AF: 0.396

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.377

Gnomad OTH AF: 0.378

GnomAD2 exomes AF: 0.438 AC: 106712 AN: 243910 AF XY: 0.438

Gnomad AFR exome AF: 0.306

Gnomad AMR exome AF: 0.528

Gnomad ASJ exome AF: 0.337

Gnomad EAS exome AF: 0.743

Gnomad FIN exome AF: 0.395

Gnomad NFE exome AF: 0.374

Gnomad OTH exome AF: 0.397

GnomAD4 exome AF: 0.401 AC: 583244 AN: 1455798 Hom.: 121815 Cov.: 39 AF XY: 0.404 AC XY: 292222 AN XY: 723872

African (AFR) AF: 0.307 AC: 10233 AN: 33372

American (AMR) AF: 0.515 AC: 22659 AN: 43972

Ashkenazi Jewish (ASJ) AF: 0.329 AC: 8566 AN: 26030

East Asian (EAS) AF: 0.783 AC: 31005 AN: 39600

South Asian (SAS) AF: 0.524 AC: 44839 AN: 85498

European-Finnish (FIN) AF: 0.401 AC: 21297 AN: 53128

Middle Eastern (MID) AF: 0.328 AC: 1747 AN: 5328

European-Non Finnish (NFE) AF: 0.378 AC: 418696 AN: 1108726

Other (OTH) AF: 0.402 AC: 24202 AN: 60144

GnomAD4 genome AF: 0.384 AC: 58365 AN: 151964 Hom.: 11845 Cov.: 32 AF XY: 0.392 AC XY: 29118 AN XY: 74290

African (AFR) AF: 0.312 AC: 12928 AN: 41440

American (AMR) AF: 0.446 AC: 6811 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.343 AC: 1189 AN: 3464

East Asian (EAS) AF: 0.746 AC: 3844 AN: 5156

South Asian (SAS) AF: 0.524 AC: 2527 AN: 4818

European-Finnish (FIN) AF: 0.396 AC: 4172 AN: 10540

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.377 AC: 25620 AN: 67958

Other (OTH) AF: 0.382 AC: 806 AN: 2112

Alfa AF: 0.384 Hom.: 47871

Bravo AF: 0.382

Asia WGS AF: 0.577 AC: 2003 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

von Willebrand disease type 2 Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

von Willebrand disease type 3 Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

von Willebrand disease type 1 Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary von Willebrand disease Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	11
DANN	Benign	0.50
PhyloP100		2.0
Mutation Taster		=68/32	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000010
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs216902; hg19: chr12-6105387; COSMIC: COSV54620567;