chrX-53199068-C-G

Variant names:

• chrX-53199068-C-G
• rs878853141
• NM_004187.5:c.2152G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The NM_004187.5(KDM5C):​c.2152G>C​(p.Ala718Pro) variant causes a missense 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. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: KDM5C NM_004187.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.82

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]

MIR6894 (HGNC:49938): (microRNA 6894) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the KDM5C gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 36 curated pathogenic missense variants (we use a threshold of 10). The gene has 40 curated benign missense variants. Gene score misZ: 5.1452 (above the threshold of 3.09). GenCC associations: The gene is linked to X-linked syndromic intellectual disability, syndromic X-linked intellectual disability Claes-Jensen type.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947
• PP5: Variant X-53199068-C-G is Pathogenic according to our data. Variant chrX-53199068-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 235844.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-53199068-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDM5C	NM_004187.5	c.2152G>C	p.Ala718Pro	missense_variant	Exon 15 of 26	ENST00000375401.8	NP_004178.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDM5C	ENST00000375401.8	c.2152G>C	p.Ala718Pro	missense_variant	Exon 15 of 26	1	NM_004187.5	ENSP00000364550.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability Pathogenic:1

Jul 25, 2014

Diagnostic Laboratory, Strasbourg University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	.;D;.;.;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.2	.;M;.;M;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-4.0	D;D;D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		1.0	.;D;.;.;.
Vest4		0.95
MutPred		0.77		.;Gain of helix (P = 0.132);.;Gain of helix (P = 0.132);.;
MVP		0.99
MPC		2.8
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		1.0
gMVP		0.99

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

Publications

LitVar

Other links and lift over

dbSNP: rs878853141; hg19: chrX-53228250;