rs199518864

Variant names:

• chr12-14789091-C-A
• rs199518864
• NM_016312.3:c.1352G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-14789091-C-A
• chr12-14789091-C-T

Variant summary

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

The NM_016312.3(WBP11):​c.1352G>T​(p.Arg451Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000729 in 1,372,436 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R451Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: WBP11 NM_016312.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.29
• Publications: 0 publications found

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]

GUCY2C-AS1 (HGNC:56054): (GUCY2C antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016312.3. 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
	WBP11	NM_016312.3	MANE Select	c.1352G>T	p.Arg451Leu	missense	Exon 11 of 12	NP_057396.1	Q9Y2W2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WBP11	ENST00000261167.7	TSL:1 MANE Select	c.1352G>T	p.Arg451Leu	missense	Exon 11 of 12	ENSP00000261167.2	Q9Y2W2
	WBP11	ENST00000858075.1		c.1352G>T	p.Arg451Leu	missense	Exon 12 of 13	ENSP00000528134.1
	WBP11	ENST00000918140.1		c.1352G>T	p.Arg451Leu	missense	Exon 11 of 12	ENSP00000588199.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.29e-7 AC: 1 AN: 1372436 Hom.: 0 Cov.: 32 AF XY: 0.00000147 AC XY: 1 AN XY: 680474

⚠️ 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: 27058

American (AMR) AF: 0.00 AC: 0 AN: 24406

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23112

East Asian (EAS) AF: 0.00 AC: 0 AN: 32564

South Asian (SAS) AF: 0.00 AC: 0 AN: 70010

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52740

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5506

European-Non Finnish (NFE) AF: 9.26e-7 AC: 1 AN: 1080372

Other (OTH) AF: 0.00 AC: 0 AN: 56668

⚠️ 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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.040	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.3
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.62
Sift	Benign	0.15	T
Sift4G	Uncertain	0.017	D
Polyphen		0.99	D
Vest4		0.80
MutPred		0.38		Loss of methylation at R451 (P = 0.0092)
MVP		0.15
MPC		0.72
ClinPred		0.96	D
GERP RS		4.7
Varity_R		0.29
gMVP		0.51
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199518864; hg19: chr12-14942025;