Genetic Variant VWA8:p.Leu937Leu (chr13-41721523-G-A) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_015058.2(VWA8):c.2811C>T(p.Leu937Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00606 in 1,613,768 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0048 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0062 ( 49 hom. )

Consequence

VWA8
NM_015058.2 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.81

Publications

2 publications found

Variant links:

Genes affected

VWA8 (HGNC:29071): (von Willebrand factor A domain containing 8) Predicted to enable ATP binding activity. Located in mitochondrion and peroxisome. [provided by Alliance of Genome Resources, Apr 2022]

VWA8 Gene-Disease associations (from GenCC):

retinitis pigmentosa 97
Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

VWA8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 13-41721523-G-A is Benign according to our data. Variant chr13-41721523-G-A is described in ClinVar as Benign. ClinVar VariationId is 784677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.81 with no splicing effect.

BS2

High AC in GnomAd4 at 727 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015058.2. 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
	VWA8	NM_015058.2	MANE Select	c.2811C>T	p.Leu937Leu	synonymous	Exon 25 of 45	NP_055873.1	A3KMH1-1
	VWA8	NM_001009814.2		c.2811C>T	p.Leu937Leu	synonymous	Exon 25 of 26	NP_001009814.1	A3KMH1-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VWA8	ENST00000379310.8	TSL:2 MANE Select	c.2811C>T	p.Leu937Leu	synonymous	Exon 25 of 45	ENSP00000368612.3	A3KMH1-1
VWA8	ENST00000281496.6	TSL:1	c.2811C>T	p.Leu937Leu	synonymous	Exon 25 of 26	ENSP00000281496.6	A3KMH1-2
VWA8	ENST00000938853.1		c.2811C>T	p.Leu937Leu	synonymous	Exon 25 of 45	ENSP00000608912.1

Frequencies

GnomAD3 genomes

AF:

0.00479

AC:

728

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000821

Gnomad AMI

AF:

0.0253

Gnomad AMR

AF:

0.00367

Gnomad ASJ

AF:

0.00982

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00800

Gnomad OTH

AF:

0.00911

GnomAD2 exomes

AF:

0.00451

AC:

1132

AN:

250838

AF XY:

0.00462

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00243

Gnomad ASJ exome

AF:

0.0116

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00111

Gnomad NFE exome

AF:

0.00733

Gnomad OTH exome

AF:

0.00768

GnomAD4 exome

AF:

0.00620

AC:

9059

AN:

1461522

Hom.:

Cov.:

AF XY:

0.00617

AC XY:

4489

AN XY:

727062

show subpopulations

African (AFR)

AF:

0.000777

AC:

AN:

33446

American (AMR)

AF:

0.00273

AC:

122

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

300

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000672

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00109

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.0127

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00726

AC:

8075

AN:

1111784

Other (OTH)

AF:

0.00575

AC:

347

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

515

1029

1544

2058

2573

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

300

600

900

1200

1500

<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:

0.00478

AC:

727

AN:

152246

Hom.:

Cov.:

AF XY:

0.00455

AC XY:

339

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.000818

AC:

AN:

41544

American (AMR)

AF:

0.00366

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00982

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000415

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00798

AC:

543

AN:

68020

Other (OTH)

AF:

0.00901

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

113

151

189

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00552

Hom.:

Bravo

AF:

0.00484

Asia WGS

AF:

0.000289

AC:

AN:

3476

EpiCase

AF:

0.00786

EpiControl

AF:

0.00741

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.75

(source)

DANN

Benign

0.60

PhyloP100

-1.8

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over