rs116243373

Variant names:

• chr12-6022084-G-A
• rs116243373
• NM_000552.5:c.3539-49C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-6022084-G-A
• chr12-6022084-G-C
• chr12-6022084-G-T

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.3539-49C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,612,620 control chromosomes in the GnomAD database, including 1,884 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (1004 hom., cov: 31)
  • Exomes 𝑓: 0.0068 (880 hom.)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.14
• Publications: 2 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 2

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• von Willebrand disease type 2B

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• von Willebrand disease 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• 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=-0.93).
• BP6: Variant 12-6022084-G-A is Benign according to our data. Variant chr12-6022084-G-A is described in ClinVar as Benign. ClinVar VariationId is 256672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.214 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.3539-49C>T		intron	N/A	NP_000543.3	P04275-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	ENST00000261405.10	TSL:1 MANE Select	c.3539-49C>T		intron	N/A	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.3539-49C>T		intron	N/A	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2967+7258C>T		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.0639 AC: 9716 AN: 152034 Hom.: 1001 Cov.: 31

Gnomad AFR AF: 0.218

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0312

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00131

Gnomad OTH AF: 0.0612

GnomAD2 exomes AF: 0.0169 AC: 4246 AN: 250952 AF XY: 0.0127

Gnomad AFR exome AF: 0.221

Gnomad AMR exome AF: 0.0137

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00127

Gnomad OTH exome AF: 0.00864

GnomAD4 exome AF: 0.00678 AC: 9902 AN: 1460468 Hom.: 880 Cov.: 31 AF XY: 0.00590 AC XY: 4288 AN XY: 726566

African (AFR) AF: 0.222 AC: 7402 AN: 33324

American (AMR) AF: 0.0151 AC: 675 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26130

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39690

South Asian (SAS) AF: 0.000464 AC: 40 AN: 86156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.0158 AC: 80 AN: 5062

European-Non Finnish (NFE) AF: 0.000712 AC: 792 AN: 1111766

Other (OTH) AF: 0.0150 AC: 907 AN: 60274

GnomAD4 genome AF: 0.0640 AC: 9741 AN: 152152 Hom.: 1004 Cov.: 31 AF XY: 0.0616 AC XY: 4583 AN XY: 74384

African (AFR) AF: 0.218 AC: 9026 AN: 41452

American (AMR) AF: 0.0311 AC: 476 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00131 AC: 89 AN: 68024

Other (OTH) AF: 0.0606 AC: 128 AN: 2112

Alfa AF: 0.0347 Hom.: 212

Bravo AF: 0.0739

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.22
DANN	Benign	0.47
PhyloP100		-1.1
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: rs116243373; hg19: chr12-6131250;