dbSNP rs216312: VWF:c.3675-75A>G (chr12-6019818-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000552.5(VWF):c.3675-75A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.569 in 1,486,220 control chromosomes in the GnomAD database, including 243,405 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.62 ( 30433 hom., cov: 32)

Exomes 𝑓: 0.56 ( 212972 hom. )

Consequence

VWF
NM_000552.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.100

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.97).

BP6

Variant 12-6019818-T-C is Benign according to our data. Variant chr12-6019818-T-C is described in ClinVar as [Benign]. Clinvar id is 1241069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6019818-T-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.756 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5 link	c.3675-75A>G		intron_variant	Intron 27 of 51	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 link	c.3675-75A>G		intron_variant	Intron 27 of 51		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
VWF	ENST00000261405.10 link	c.3675-75A>G	intron_variant	Intron 27 of 51	1	NM_000552.5	ENSP00000261405.5	P04275-1
VWF	ENST00000538635.5 link	n.421-25884A>G	intron_variant	Intron 5 of 5	4
VWF	ENST00000539641.1 link	n.473-75A>G	intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.624

AC:

94775

AN:

151912

Hom.:

30387

Cov.:

show subpopulations

Gnomad AFR

AF:

0.763

Gnomad AMI

AF:

0.625

Gnomad AMR

AF:

0.682

Gnomad ASJ

AF:

0.643

Gnomad EAS

AF:

0.631

Gnomad SAS

AF:

0.600

Gnomad FIN

AF:

0.473

Gnomad MID

AF:

0.712

Gnomad NFE

AF:

0.549

Gnomad OTH

AF:

0.634

GnomAD4 exome

AF:

0.562

AC:

750239

AN:

1334190

Hom.:

212972

AF XY:

0.562

AC XY:

372277

AN XY:

662154

show subpopulations

Gnomad4 AFR exome

AF:

0.773

AC:

23839

AN:

30828

Gnomad4 AMR exome

AF:

0.728

AC:

25981

AN:

35678

Gnomad4 ASJ exome

AF:

0.638

AC:

15843

AN:

24828

Gnomad4 EAS exome

AF:

0.625

AC:

22600

AN:

36138

Gnomad4 SAS exome

AF:

0.585

AC:

45608

AN:

77976

Gnomad4 FIN exome

AF:

0.477

AC:

18649

AN:

39068

Gnomad4 NFE exome

AF:

0.546

AC:

562213

AN:

1029556

Gnomad4 Remaining exome

AF:

0.585

AC:

32739

AN:

55980

Heterozygous variant carriers

17923

35846

53770

71693

89616

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

15942

31884

47826

63768

79710

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.624

AC:

94876

AN:

152030

Hom.:

30433

Cov.:

AF XY:

0.624

AC XY:

46340

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.763

AC:

0.762891

AN:

0.762891

Gnomad4 AMR

AF:

0.683

AC:

0.682675

AN:

0.682675

Gnomad4 ASJ

AF:

0.643

AC:

0.643145

AN:

0.643145

Gnomad4 EAS

AF:

0.631

AC:

0.631344

AN:

0.631344

Gnomad4 SAS

AF:

0.599

AC:

0.599168

AN:

0.599168

Gnomad4 FIN

AF:

0.473

AC:

0.47259

AN:

0.47259

Gnomad4 NFE

AF:

0.549

AC:

0.549349

AN:

0.549349

Gnomad4 OTH

AF:

0.632

AC:

0.631629

AN:

0.631629

Heterozygous variant carriers

1782

3564

5345

7127

8909

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

776

1552

2328

3104

3880

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.579

Hom.:

55668

Bravo

AF:

0.648

Asia WGS

AF:

0.650

AC:

2258

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 19, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

3.7

DANN

Benign

0.43

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over