8-86402014-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_007013.4(WWP1):c.540-5T>C variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.01994
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.199

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 2658677.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 344 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WWP1	NM_007013.4	c.540-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000517970.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WWP1	ENST00000517970.6	c.540-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_007013.4	P1
WWP1	ENST00000265428.4	c.540-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		P1
WWP1	ENST00000518683.5	n.378+3376T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00226 AC: 344 AN: 152198 Hom.: 3 Cov.: 33

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

GnomAD3 exomes AF: 0.00236 AC: 511 AN: 216168 Hom.: 2 AF XY: 0.00234 AC XY: 276 AN XY: 117902

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 SAS exome AF: 0.000119

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.: 4 Cov.: 31 AF XY: 0.00134 AC XY: 931 AN XY: 693158

Gnomad4 AFR exome AF: 0.0000651

Gnomad4 AMR exome AF: 0.000238

Gnomad4 ASJ exome AF: 0.0000833

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000525

Gnomad4 FIN exome AF: 0.00966

Gnomad4 NFE exome AF: 0.00111

Gnomad4 OTH exome AF: 0.00117

GnomAD4 genome AF: 0.00226 AC: 344 AN: 152316 Hom.: 3 Cov.: 33 AF XY: 0.00271 AC XY: 202 AN XY: 74478

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0135

Gnomad4 NFE AF: 0.00265

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00203 Hom.: 1

Bravo AF: 0.00104

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2023

WWP1: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	9.9
Dann	Benign	0.60

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

LitVar

Other links and lift over

dbSNP: rs187132881; hg19: chr8-87414243;