Genetic Variant WWP1:c.540-5T>C (chr8-86402014-T-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_007013.4(WWP1):c.540-5T>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 0.00137 in 1,549,278 control chromosomes in the GnomAD database, including 7 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 Likely benign (★).

Frequency

Genomes: 𝑓 0.0023 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 4 hom. )

Consequence

WWP1
NM_007013.4 splice_region, intron

Scores

Splicing: ADA: 0.01994

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.199

Publications

2 publications found

Variant links:

Genes affected

WWP1 (HGNC:17004): (WW domain containing E3 ubiquitin protein ligase 1) WW domain-containing proteins are found in all eukaryotes and play an important role in the regulation of a wide variety of cellular functions such as protein degradation, transcription, and RNA splicing. This gene encodes a protein which contains 4 tandem WW domains and a HECT (homologous to the E6-associated protein carboxyl terminus) domain. The encoded protein belongs to a family of NEDD4-like proteins, which are E3 ubiquitin-ligase molecules and regulate key trafficking decisions, including targeting of proteins to proteosomes or lysosomes. Alternative splicing of this gene generates at least 6 transcript variants; however, the full length nature of these transcripts has not been defined. [provided by RefSeq, Jul 2008]

WWP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 8-86402014-T-C is Benign according to our data. Variant chr8-86402014-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2658677.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 344 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007013.4. 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
	WWP1	NM_007013.4	MANE Select	c.540-5T>C		splice_region intron	N/A	NP_008944.1	Q9H0M0-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
WWP1	ENST00000517970.6	TSL:1 MANE Select	c.540-5T>C	splice_region intron	N/A	ENSP00000427793.1	Q9H0M0-1
WWP1	ENST00000265428.4	TSL:1	c.540-5T>C	splice_region intron	N/A	ENSP00000265428.4	Q9H0M0-1
WWP1	ENST00000518683.5	TSL:1	n.378+3376T>C	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00226

AC:

344

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0135

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00265

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00236

AC:

511

AN:

216168

AF XY:

0.00234

show subpopulations

Gnomad AFR exome

AF:

0.000218

Gnomad AMR exome

AF:

0.000188

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0107

Gnomad NFE exome

AF:

0.00254

Gnomad OTH exome

AF:

0.00341

GnomAD4 exome

AF:

0.00127

AC:

1780

AN:

1396962

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

931

AN XY:

693158

show subpopulations

African (AFR)

AF:

0.0000651

AC:

AN:

30732

American (AMR)

AF:

0.000238

AC:

AN:

37762

Ashkenazi Jewish (ASJ)

AF:

0.0000833

AC:

AN:

24022

East Asian (EAS)

AF:

0.00

AC:

AN:

36666

South Asian (SAS)

AF:

0.0000525

AC:

AN:

76160

European-Finnish (FIN)

AF:

0.00966

AC:

498

AN:

51574

Middle Eastern (MID)

AF:

0.000553

AC:

AN:

5422

European-Non Finnish (NFE)

AF:

0.00111

AC:

1195

AN:

1077472

Other (OTH)

AF:

0.00117

AC:

AN:

57152

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

185

278

370

463

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.00226

AC:

344

AN:

152316

Hom.:

Cov.:

AF XY:

0.00271

AC XY:

202

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41576

American (AMR)

AF:

0.000719

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0135

AC:

143

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00265

AC:

180

AN:

68022

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00203

Hom.:

Bravo

AF:

0.00104

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

9.9

(source)

DANN

Benign

0.60

PhyloP100

0.20

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.020

dbscSNV1_RF

Benign

0.056

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