rs113446850

Variant names:

• chr12-6023624-T-G
• rs113446850
• NM_000552.5:c.3379+7A>C

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.3379+7A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.017 in 1,613,554 control chromosomes in the GnomAD database, including 3,816 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.089 (2014 hom., cov: 31)
  • Exomes 𝑓: 0.0095 (1802 hom.)
• Consequence: VWF NM_000552.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001811
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0730
• 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 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=-0.78).
• BP6: Variant 12-6023624-T-G is Benign according to our data. Variant chr12-6023624-T-G is described in ClinVar as Benign. ClinVar VariationId is 256666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.301 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.3379+7A>C		splice_region intron	N/A	NP_000543.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	ENST00000261405.10	TSL:1 MANE Select	c.3379+7A>C		splice_region intron	N/A	ENSP00000261405.5
	VWF	ENST00000538635.5	TSL:4	n.421-29690A>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0893 AC: 13589 AN: 152162 Hom.: 2010 Cov.: 31

Gnomad AFR AF: 0.306

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0398

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00154

Gnomad OTH AF: 0.0808

GnomAD2 exomes AF: 0.0234 AC: 5837 AN: 249030 AF XY: 0.0174

Gnomad AFR exome AF: 0.309

Gnomad AMR exome AF: 0.0181

Gnomad ASJ exome AF: 0.00413

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00136

Gnomad OTH exome AF: 0.0122

GnomAD4 exome AF: 0.00948 AC: 13856 AN: 1461274 Hom.: 1802 Cov.: 32 AF XY: 0.00818 AC XY: 5949 AN XY: 726908

African (AFR) AF: 0.315 AC: 10518 AN: 33424

American (AMR) AF: 0.0207 AC: 925 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00358 AC: 93 AN: 26004

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000709 AC: 61 AN: 86002

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.0207 AC: 119 AN: 5754

European-Non Finnish (NFE) AF: 0.000775 AC: 862 AN: 1111932

Other (OTH) AF: 0.0212 AC: 1278 AN: 60354

GnomAD4 genome AF: 0.0894 AC: 13618 AN: 152280 Hom.: 2014 Cov.: 31 AF XY: 0.0862 AC XY: 6422 AN XY: 74466

African (AFR) AF: 0.306 AC: 12697 AN: 41518

American (AMR) AF: 0.0397 AC: 608 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.00154 AC: 105 AN: 68038

Other (OTH) AF: 0.0799 AC: 169 AN: 2114

Alfa AF: 0.0628 Hom.: 280

Bravo AF: 0.103

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	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	-0.78
CADD	Benign	5.2
DANN	Benign	0.54
PhyloP100		-0.073
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000018
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.030		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: rs113446850; hg19: chr12-6132790;