12-6011792-G-A

Variant names:

• chr12-6011792-G-A
• rs56981471
• NM_000552.5:c.5667C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000552.5(VWF):​c.5667C>T​(p.Pro1889Pro) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00415 in 1,609,390 control chromosomes in the GnomAD database, including 165 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1889P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.020 (76 hom., cov: 31)
  • Exomes 𝑓: 0.0026 (89 hom.)
• Consequence: VWF NM_000552.5 splice_region, synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0420
• Publications: 1 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 12-6011792-G-A is Benign according to our data. Variant chr12-6011792-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.042 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0631 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.5667C>T	p.Pro1889Pro	splice_region synonymous	Exon 34 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.5667C>T	p.Pro1889Pro	splice_region synonymous	Exon 34 of 52	ENSP00000261405.5
	VWF	ENST00000538635.5	TSL:4	n.421-17858C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0195 AC: 2963 AN: 151846 Hom.: 77 Cov.: 31

Gnomad AFR AF: 0.0653

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00958

Gnomad ASJ AF: 0.00693

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.0144

GnomAD2 exomes AF: 0.00531 AC: 1231 AN: 231986 AF XY: 0.00409

Gnomad AFR exome AF: 0.0692

Gnomad AMR exome AF: 0.00415

Gnomad ASJ exome AF: 0.00574

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000867

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00255 AC: 3722 AN: 1457426 Hom.: 89 Cov.: 29 AF XY: 0.00224 AC XY: 1627 AN XY: 725284

African (AFR) AF: 0.0697 AC: 2324 AN: 33358

American (AMR) AF: 0.00453 AC: 202 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.00572 AC: 149 AN: 26040

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.000500 AC: 43 AN: 86042

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53318

Middle Eastern (MID) AF: 0.00929 AC: 53 AN: 5704

European-Non Finnish (NFE) AF: 0.000578 AC: 641 AN: 1108534

Other (OTH) AF: 0.00513 AC: 309 AN: 60184

GnomAD4 genome AF: 0.0195 AC: 2965 AN: 151964 Hom.: 76 Cov.: 31 AF XY: 0.0187 AC XY: 1388 AN XY: 74250

African (AFR) AF: 0.0651 AC: 2697 AN: 41414

American (AMR) AF: 0.00956 AC: 146 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00693 AC: 24 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000986 AC: 67 AN: 67982

Other (OTH) AF: 0.0142 AC: 30 AN: 2108

Alfa AF: 0.00836 Hom.: 12

Bravo AF: 0.0226

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hereditary von Willebrand disease (1)
-	-	1	not specified (1)
-	-	1	von Willebrand disease type 1 (1)
-	-	1	von Willebrand disease type 2 (1)
-	-	1	von Willebrand disease type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	3.7
DANN	Benign	0.83
PhyloP100		0.042
Mutation Taster		=91/9	polymorphism (auto)

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

Other links and lift over

dbSNP: rs56981471; hg19: chr12-6120958; COSMIC: COSV54628341;