NM_007013.4:c.1082C>G

Variant names:

• chr8-86425243-C-G
• rs1809552275
• NM_007013.4:c.1082C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_007013.4(WWP1):​c.1082C>G​(p.Pro361Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: WWP1 NM_007013.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.30
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806

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.1082C>G	p.Pro361Arg	missense	Exon 10 of 25	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.1082C>G	p.Pro361Arg	missense	Exon 10 of 25	ENSP00000427793.1	Q9H0M0-1
	WWP1	ENST00000265428.4	TSL:1	c.1082C>G	p.Pro361Arg	missense	Exon 8 of 23	ENSP00000265428.4	Q9H0M0-1
	WWP1	ENST00000518683.5	TSL:1	n.736C>G		non_coding_transcript_exon	Exon 6 of 15

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458294 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725362

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33324

American (AMR) AF: 0.00 AC: 0 AN: 44190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26036

East Asian (EAS) AF: 0.00 AC: 0 AN: 39514

South Asian (SAS) AF: 0.00 AC: 0 AN: 85270

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110702

Other (OTH) AF: 0.00 AC: 0 AN: 60218

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.071	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.048	D
MutationAssessor	Benign	1.7	L
PhyloP100		3.3
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.67
Sift	Benign	0.13	T
Sift4G	Benign	0.29	T
Polyphen		0.96	D
Vest4		0.71
MutPred		0.52		Gain of MoRF binding (P = 7e-04)
MVP		0.52
MPC		0.54
ClinPred		0.98	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.20
gMVP		0.50
Mutation Taster		=72/28	polymorphism

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

Other links and lift over

dbSNP: rs1809552275; hg19: chr8-87437472;