NM_012478.4:c.487A>C

Variant names:

• chr17-75847841-T-G
• rs1555604710
• NM_012478.4:c.487A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012478.4(WBP2):​c.487A>C​(p.Met163Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as no classifications from unflagged records (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: WBP2 NM_012478.4 missense
• Clinical Significance: no classifications from unflagged records no classifications from unflagged records P:1
• Conservation: PhyloP100: 2.50
• Publications: 1 publications found

Genes affected

WBP2 (HGNC:12738): (WW domain binding protein 2) The globular WW domain is composed of 38 to 40 semiconserved amino acids shared by proteins of diverse functions including structural, regulatory, and signaling proteins. The domain is involved in mediating protein-protein interactions through the binding of polyproline ligands. This gene encodes a WW domain binding protein that is a transcriptional coactivator of estrogen receptor alpha and progesterone receptor. Defects in this gene have been associated with hearing impairment. [provided by RefSeq, Jan 2017]

WBP2 Gene-Disease associations (from GenCC):

• hearing loss, autosomal recessive 107

  Inheritance: AR, Unknown Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2271018).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WBP2	NM_012478.4	c.487A>C	p.Met163Leu	missense_variant	Exon 5 of 8	ENST00000254806.8	NP_036610.2
WBP2	NM_001348170.1	c.487A>C	p.Met163Leu	missense_variant	Exon 6 of 9		NP_001335099.1
WBP2	XM_047435712.1	c.421A>C	p.Met141Leu	missense_variant	Exon 5 of 8		XP_047291668.1
WBP2	NM_001330499.2	c.398-232A>C		intron_variant	Intron 4 of 6		NP_001317428.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WBP2	ENST00000254806.8	c.487A>C	p.Met163Leu	missense_variant	Exon 5 of 8	1	NM_012478.4	ENSP00000254806.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: no classifications from unflagged records

Submissions summary: Pathogenic:1

Revision: no classifications from unflagged records

Submissions by phenotype

Hearing loss, autosomal recessive 107 Pathogenic:1

Aug 24, 2017

OMIM

Significance: Pathogenic

Review Status: flagged submission

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Benign	0.88
DEOGEN2	Benign	0.044	T;T;T;T;.;.;T;T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.28
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D;D;D;.;D;T;T;T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.23	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M;.;.;M;.;.;.;.
PhyloP100		2.5
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.99	N;.;.;.;.;.;.;.
REVEL	Benign	0.069
Sift	Benign	0.26	T;.;.;.;.;.;.;.
Sift4G	Benign	0.57	T;T;T;T;T;.;T;T
Polyphen		0.058	B;.;.;B;.;.;.;.
Vest4		0.25
MutPred		0.54		Gain of glycosylation at P167 (P = 0.2109);Gain of glycosylation at P167 (P = 0.2109);.;Gain of glycosylation at P167 (P = 0.2109);Gain of glycosylation at P167 (P = 0.2109);.;.;.;
MVP		0.41
MPC		0.18
ClinPred		0.28	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.41
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs1555604710; hg19: chr17-73843922;