chr1-68153618-C-G
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_024911.7(WLS):c.702G>C(p.Trp234Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000366 in 1,614,084 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: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000038 ( 0 hom. )
Consequence
WLS
NM_024911.7 missense
NM_024911.7 missense
Scores
11
3
3
Clinical Significance
Conservation
PhyloP100: 7.71
Genes affected
WLS (HGNC:30238): (Wnt ligand secretion mediator) Enables Wnt-protein binding activity and identical protein binding activity. Involved in positive regulation of cell communication and protein transport. Located in several cellular components, including Golgi apparatus; early endosome; and endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.96
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WLS | NM_024911.7 | c.702G>C | p.Trp234Cys | missense_variant | 5/12 | ENST00000262348.9 | |
GNG12-AS1 | NR_040077.1 | n.1228+15168C>G | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WLS | ENST00000262348.9 | c.702G>C | p.Trp234Cys | missense_variant | 5/12 | 1 | NM_024911.7 | P1 | |
GNG12-AS1 | ENST00000420587.5 | n.1213+15168C>G | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152202Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000115 AC: 29AN: 251456Hom.: 0 AF XY: 0.0000809 AC XY: 11AN XY: 135898
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GnomAD4 exome AF: 0.0000383 AC: 56AN: 1461882Hom.: 0 Cov.: 31 AF XY: 0.0000413 AC XY: 30AN XY: 727246
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74356
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Zaki syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant c.702G>C(p.Trp234Cys) in WLS gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Trp234Cys variant has allele frequency 0.01% in gnomAD exomes and novel (not in any individuals) in 1000 Genomes. This variant has not been reported to the ClinVar database. The amino acid Trp at position 234 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Trp234Cys in WLS is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance (VUS). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;D
Sift4G
Pathogenic
D;D;D;.;.;.
Polyphen
D;D;.;.;.;.
Vest4
MutPred
0.94
.;Loss of catalytic residue at M237 (P = 0.0078);.;.;.;.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at