chr10-1080454-C-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM5PP5_Very_Strong
The NM_014023.4(WDR37):c.374C>T(p.Thr125Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T125A) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
WDR37
NM_014023.4 missense
NM_014023.4 missense
Scores
6
9
3
Clinical Significance
Conservation
PhyloP100: 7.76
Genes affected
WDR37 (HGNC:31406): (WD repeat domain 37) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr10-1080453-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1199795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP5
?
Variant 10-1080454-C-T is Pathogenic according to our data. Variant chr10-1080454-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 440948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-1080454-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WDR37 | NM_014023.4 | c.374C>T | p.Thr125Ile | missense_variant | 5/14 | ENST00000263150.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WDR37 | ENST00000263150.9 | c.374C>T | p.Thr125Ile | missense_variant | 5/14 | 1 | NM_014023.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neurooculocardiogenitourinary syndrome Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 05, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Undiagnosed Diseases Network, NIH | Aug 01, 2019 | - - |
Congenital cerebellar hypoplasia Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | - | - - |
WDR37-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 02, 2024 | The WDR37 c.374C>T variant is predicted to result in the amino acid substitution p.Thr125Ile. This variant has been reported in the de novo state in multiple individuals with WDR37-related diseases (Reis et al. 2019. PubMed ID: 31327510; Kanca et al. 2019. PubMed ID: 31327508; Aldinger et al. 2019. PubMed ID: 31474318. Table S5; Zhu et al. 2022. PubMed ID: 35726512). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. - |
Cerebellar vermis hypoplasia;C3278923:Ventriculomegaly Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Dobyns Lab, Seattle Children's Research Institute | Feb 18, 2019 | - - |
Congenital ocular coloboma;C0014544:Epilepsy;C0424605:Developmental delay;C1737329:Dysmorphism;C3714756:Intellectual disability;C5231391:Congenital cerebellar hypoplasia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Undiagnosed Diseases Program Translational Research Laboratory, National Institutes of Health | May 06, 2019 | - - |
not provided Other:1
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T;.;T;.;T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;.;.;.;M;.
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;.;D;.;D;D
REVEL
Uncertain
Sift
Uncertain
D;.;D;.;D;D
Sift4G
Uncertain
D;D;D;.;D;D
Polyphen
D;.;D;.;D;.
Vest4
MutPred
Gain of catalytic residue at T125 (P = 0.0262);Gain of catalytic residue at T125 (P = 0.0262);Gain of catalytic residue at T125 (P = 0.0262);Gain of catalytic residue at T125 (P = 0.0262);Gain of catalytic residue at T125 (P = 0.0262);.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at