rs199422239
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_ModeratePP5_Moderate
The NM_004187.5(KDM5C):c.229G>A(p.Ala77Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 22)
Consequence
KDM5C
NM_004187.5 missense, splice_region
NM_004187.5 missense, splice_region
Scores
9
7
1
Splicing: ADA: 0.9602
1
1
Clinical Significance
Conservation
PhyloP100: 7.84
Genes affected
KDM5C (HGNC:11114): (lysine demethylase 5C) This gene is a member of the SMCY homolog family and encodes a protein with one ARID domain, one JmjC domain, one JmjN domain and two PHD-type zinc fingers. The DNA-binding motifs suggest this protein is involved in the regulation of transcription and chromatin remodeling. Mutations in this gene have been associated with X-linked cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2009]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 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), KDM5C. . Gene score misZ: 5.1452 (greater than the threshold 3.09). The gene has 36 curated pathogenic missense variants (we use a threshold of 10). The gene has 40 curated benign missense variants. GenCC has associacion of the gene with X-linked syndromic intellectual disability, syndromic X-linked intellectual disability Claes-Jensen type.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.842
PP5
Variant X-53218398-C-T is Pathogenic according to our data. Variant chrX-53218398-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9778.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD3 genomes
Cov.:
22
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome Cov.: 22
GnomAD4 genome
Cov.:
22
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 13, 2016 | The p.A77T variant (also known as c.229G>A) is located in coding exon 3 of the KDM5C gene. This alteration results from a G to A substitution at nucleotide position 229. The alanine at codon 77 is replaced by threonine, an amino acid with similar properties. This change occurs in the first base pair of coding exon 3. This alteration was observed to track with disease in one family with seven affected individuals, three males and four females with skewed X-inactivation, and was not detected in 2 unaffected females; clinical features in this family included intellectual disability, short stature, strabismus, broad hands, and hyperreflexia (Abidi FE et al. J Med Genet. 2008; 45(12):787-93). A computational analysis found this alteration, which is located in the ARID domain, did not affect the DNA binding of this domain and authors suggest the mechanism of disease is not related to DNA binding (Peng et al. Int J Mol Sci. 2015;16(11):27270-87). This variant was previously reported in the SNPDatabase as rs199422239. This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), 1000 Genomes Project and ExAC. In the ESP, this variant was not observed in 6,503 samples with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Syndromic X-linked intellectual disability Claes-Jensen type Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2008 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;M
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;.;.
Vest4
MutPred
Loss of ubiquitination at K82 (P = 0.0818);Loss of ubiquitination at K82 (P = 0.0818);Loss of ubiquitination at K82 (P = 0.0818);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at