chr8-86411757-C-A

Variant names:

• chr8-86411757-C-A
• NM_007013.4:c.944C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_007013.4(WWP1):​c.944C>A​(p.Thr315Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: WWP1 NM_007013.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.548
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.040332258).

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.944C>A	p.Thr315Asn	missense	Exon 9 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.944C>A	p.Thr315Asn	missense	Exon 9 of 25	ENSP00000427793.1	Q9H0M0-1
	WWP1	ENST00000265428.4	TSL:1	c.944C>A	p.Thr315Asn	missense	Exon 7 of 23	ENSP00000265428.4	Q9H0M0-1
	WWP1	ENST00000518683.5	TSL:1	n.598C>A		non_coding_transcript_exon	Exon 5 of 15

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461784 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727196

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111928

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

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	0.068
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	10
DANN	Benign	0.91
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.55
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.058
Sift	Benign	0.30	T
Sift4G	Benign	0.24	T
Polyphen		0.0030	B
Vest4		0.087
MutPred		0.16		Loss of phosphorylation at T315 (P = 0.0311)
MVP		0.068
MPC		0.12
ClinPred		0.12	T
GERP RS		2.4
Varity_R		0.060
gMVP		0.18
Mutation Taster		=85/15	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

hg19: chr8-87423986;