12-14787498-C-A

Position:

• chr12-14787498-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_016312.3(WBP11):​c.1493G>T​(p.Gly498Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000149 in 1,342,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: WBP11 NM_016312.3 missense, splice_region
• Scores: Splicing: ADA: 0.9995
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.35

Genes affected

WBP11 (HGNC:16461): (WW domain binding protein 11) This gene encodes a nuclear protein, which colocalizes with mRNA splicing factors and intermediate filament-containing perinuclear networks. This protein has 95% amino acid sequence identity to the mouse Wbp11 protein. It contains two proline-rich regions that bind to the WW domain of Npw38, a nuclear protein, and thus this protein is also called Npw38-binding protein NpwBP. The Npw38-NpwBP complex may function as a component of an mRNA factory in the nucleus. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), WBP11. . Gene score misZ 2.9803 (greater than the threshold 3.09). Trascript score misZ 3.4119 (greater than threshold 3.09). GenCC has associacion of gene with vertebral, cardiac, tracheoesophageal, renal, and limb defects.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.752

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WBP11	NM_016312.3	c.1493G>T	p.Gly498Val	missense_variant, splice_region_variant	12/12	ENST00000261167.7	NP_057396.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WBP11	ENST00000261167.7	c.1493G>T	p.Gly498Val	missense_variant, splice_region_variant	12/12	1	NM_016312.3	ENSP00000261167.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000149 AC: 2 AN: 1342390 Hom.: 0 Cov.: 30 AF XY: 0.00000306 AC XY: 2 AN XY: 654330

Gnomad4 AFR exome AF: 0.0000334

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000181

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2023

The c.1493G>T (p.G498V) alteration is located in exon 12 (coding exon 11) of the WBP11 gene. This alteration results from a G to T substitution at nucleotide position 1493, causing the glycine (G) at amino acid position 498 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	29
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.081	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Uncertain	2.3	M
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.60
Sift	Benign	0.062	T
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.40		Loss of relative solvent accessibility (P = 0.0186);
MVP		0.19
MPC		0.73
ClinPred		0.88	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.26
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
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: rs1949766435; hg19: chr12-14940432;