NM_007013.4:c.2395-4C>T

Variant names:

• chr8-86457917-C-T
• rs188228045
• NM_007013.4:c.2395-4C>T

Variant summary

Our verdict is Benign. The variant received -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, 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, intron
• Scores: Splicing: ADA: 0.00005210
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0660
• Publications: 3 publications found

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

Our verdict: Benign. The variant received -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 VariationId is 2658678.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 366 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.2395-4C>T		splice_region intron	N/A	NP_008944.1	Q9H0M0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWP1	ENST00000517970.6	TSL:1 MANE Select	c.2395-4C>T		splice_region intron	N/A	ENSP00000427793.1	Q9H0M0-1
	WWP1	ENST00000265428.4	TSL:1	c.2395-4C>T		splice_region intron	N/A	ENSP00000265428.4	Q9H0M0-1
	WWP1	ENST00000882789.1		c.2395-4C>T		splice_region intron	N/A	ENSP00000552848.1

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

GnomAD2 exomes AF: 0.00303 AC: 759 AN: 250878 AF XY: 0.00314

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 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

African (AFR) AF: 0.000658 AC: 22 AN: 33422

American (AMR) AF: 0.00280 AC: 125 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85966

European-Finnish (FIN) AF: 0.00174 AC: 93 AN: 53340

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5758

European-Non Finnish (NFE) AF: 0.00531 AC: 5896 AN: 1109892

Other (OTH) AF: 0.00249 AC: 150 AN: 60250

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

African (AFR) AF: 0.000578 AC: 24 AN: 41504

American (AMR) AF: 0.00105 AC: 16 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000945 AC: 10 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00459 AC: 312 AN: 67952

Other (OTH) AF: 0.00190 AC: 4 AN: 2106

Alfa AF: 0.00316 Hom.: 1

Bravo AF: 0.00232

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	11
DANN	Benign	0.71
PhyloP100		0.066
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs188228045; hg19: chr8-87470146;