8-86457917-C-T

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.2395-4C>T 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 0.00413 in 1,611,060 control chromosomes in the GnomAD database, including 16 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 0.0024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (15 hom.)
• Consequence: WWP1 NM_007013.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00005210
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0660

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=-0.62).
• BP6: Variant 8-86457917-C-T is Benign according to our data. Variant chr8-86457917-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2658678.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 366 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WWP1	NM_007013.4	c.2395-4C>T		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.2395-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_007013.4	P1
WWP1	ENST00000265428.4	c.2395-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		P1

Frequencies

GnomAD3 genomes AF: 0.00241 AC: 366 AN: 151986 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000580

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00459

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00303 AC: 759 AN: 250878 Hom.: 1 AF XY: 0.00314 AC XY: 426 AN XY: 135616

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00288

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.00528

Gnomad OTH exome AF: 0.00376

GnomAD4 exome AF: 0.00431 AC: 6292 AN: 1458956 Hom.: 15 Cov.: 30 AF XY: 0.00412 AC XY: 2994 AN XY: 725906

Gnomad4 AFR exome AF: 0.000658

Gnomad4 AMR exome AF: 0.00280

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00174

Gnomad4 NFE exome AF: 0.00531

Gnomad4 OTH exome AF: 0.00249

GnomAD4 genome AF: 0.00241 AC: 366 AN: 152104 Hom.: 1 Cov.: 32 AF XY: 0.00199 AC XY: 148 AN XY: 74366

Gnomad4 AFR AF: 0.000578

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000945

Gnomad4 NFE AF: 0.00459

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00316 Hom.: 1

Bravo AF: 0.00232

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	-0.62
Cadd	Benign	11
Dann	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000052
dbscSNV1_RF	Benign	0.0080
SpliceAI score (max)		0.020		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: rs188228045; hg19: chr8-87470146;