NM_000552.5:c.5843-111A>G

Variant names:

• chr12-5996333-T-C
• rs216903
• NM_000552.5:c.5843-111A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000552.5(VWF):​c.5843-111A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.545 in 984,014 control chromosomes in the GnomAD database, including 148,336 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24257 hom., cov: 31)
  • Exomes 𝑓: 0.54 (124079 hom.)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.84
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 12-5996333-T-C is Benign according to our data. Variant chr12-5996333-T-C is described in ClinVar as Benign. ClinVar VariationId is 1225172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.727 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	NM_000552.5	MANE Select	c.5843-111A>G		intron	N/A	NP_000543.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	ENST00000261405.10	TSL:1 MANE Select	c.5843-111A>G		intron	N/A	ENSP00000261405.5
	VWF	ENST00000895679.1		c.5843-111A>G		intron	N/A	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2967+33009A>G		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.562 AC: 85352 AN: 151846 Hom.: 24228 Cov.: 31

Gnomad AFR AF: 0.595

Gnomad AMI AF: 0.499

Gnomad AMR AF: 0.596

Gnomad ASJ AF: 0.479

Gnomad EAS AF: 0.746

Gnomad SAS AF: 0.599

Gnomad FIN AF: 0.500

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.533

Gnomad OTH AF: 0.558

GnomAD4 exome AF: 0.542 AC: 450986 AN: 832050 Hom.: 124079 AF XY: 0.545 AC XY: 234992 AN XY: 431516

African (AFR) AF: 0.580 AC: 12122 AN: 20914

American (AMR) AF: 0.602 AC: 20983 AN: 34864

Ashkenazi Jewish (ASJ) AF: 0.469 AC: 10112 AN: 21538

East Asian (EAS) AF: 0.788 AC: 26007 AN: 32994

South Asian (SAS) AF: 0.593 AC: 39527 AN: 66628

European-Finnish (FIN) AF: 0.508 AC: 24213 AN: 47672

Middle Eastern (MID) AF: 0.453 AC: 1357 AN: 2998

European-Non Finnish (NFE) AF: 0.523 AC: 295664 AN: 565380

Other (OTH) AF: 0.538 AC: 21001 AN: 39062

GnomAD4 genome AF: 0.562 AC: 85425 AN: 151964 Hom.: 24257 Cov.: 31 AF XY: 0.563 AC XY: 41798 AN XY: 74268

African (AFR) AF: 0.595 AC: 24642 AN: 41432

American (AMR) AF: 0.597 AC: 9114 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.479 AC: 1662 AN: 3470

East Asian (EAS) AF: 0.747 AC: 3852 AN: 5156

South Asian (SAS) AF: 0.598 AC: 2874 AN: 4808

European-Finnish (FIN) AF: 0.500 AC: 5277 AN: 10552

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.533 AC: 36248 AN: 67954

Other (OTH) AF: 0.560 AC: 1181 AN: 2110

Alfa AF: 0.553 Hom.: 3962

Bravo AF: 0.567

Asia WGS AF: 0.630 AC: 2194 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.75
DANN	Benign	0.48
PhyloP100		-1.8
Mutation Taster		=100/0	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: rs216903; hg19: chr12-6105499;