rs61750601

Variant names:

• chr12-6016744-G-A
• rs61750601
• NM_000552.5:c.5170+10C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-6016744-G-A
• chr12-6016744-G-C
• chr12-6016744-G-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP3 BP6 BS2_Supporting

The NM_000552.5(VWF):​c.5170+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00429 in 1,614,122 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene VWF is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0039 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (24 hom.)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6 O:1
• Conservation: PhyloP100: -2.86
• Publications: 3 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: Orphanet, ClinGen
• 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

Specifications for VWF are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 12-6016744-G-A is Benign according to our data. Variant chr12-6016744-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 100418.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.5170+10C>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.5170+10C>T		intron	N/A	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.5170+10C>T		intron	N/A	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2967+12598C>T		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.00391 AC: 595 AN: 152180 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00462

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00403 AC: 1014 AN: 251476 AF XY: 0.00405

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00289

Gnomad ASJ exome AF: 0.00675

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0127

Gnomad NFE exome AF: 0.00425

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00433 AC: 6326 AN: 1461824 Hom.: 24 Cov.: 32 AF XY: 0.00429 AC XY: 3118 AN XY: 727220

African (AFR) AF: 0.000627 AC: 21 AN: 33480

American (AMR) AF: 0.00302 AC: 135 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00666 AC: 174 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00112 AC: 97 AN: 86252

European-Finnish (FIN) AF: 0.0120 AC: 641 AN: 53420

Middle Eastern (MID) AF: 0.00452 AC: 26 AN: 5756

European-Non Finnish (NFE) AF: 0.00449 AC: 4995 AN: 1111964

Other (OTH) AF: 0.00392 AC: 237 AN: 60394

GnomAD4 genome AF: 0.00391 AC: 595 AN: 152298 Hom.: 3 Cov.: 32 AF XY: 0.00402 AC XY: 299 AN XY: 74466

African (AFR) AF: 0.00123 AC: 51 AN: 41556

American (AMR) AF: 0.00379 AC: 58 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00864 AC: 30 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4830

European-Finnish (FIN) AF: 0.0122 AC: 129 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00462 AC: 314 AN: 68030

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00329 Hom.: 2

Bravo AF: 0.00331

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (5)
-	1	-	Hereditary von Willebrand disease (1)
-	-	1	not specified (1)
-	-	1	von Willebrand disease type 1 (1)
-	-	1	von Willebrand disease type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	19
DANN	Benign	0.71
PhyloP100		-2.9
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.76		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.76		Position offset: 6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs61750601;

hg19: chr12-6125910;