rs797044474

Positions:

• chrX-53216117-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_004187.5(KDM5C):​c.738G>C​(p.Met246Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 24)
• Consequence: KDM5C NM_004187.5 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 4.92

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.22206694).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDM5C	NM_004187.5	c.738G>C	p.Met246Ile	missense_variant	6/26	ENST00000375401.8	NP_004178.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KDM5C	ENST00000375401.8	c.738G>C	p.Met246Ile	missense_variant	6/26	1	NM_004187.5	ENSP00000364550.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	.;T;.;.;.
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T;T;T;T;T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.22	T;T;T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.8	.;L;.;L;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.89	N;N;N;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.27	T;T;T;T;T
Sift4G	Benign	0.21	T;T;T;T;T
Polyphen		0.0090	.;B;.;.;.
Vest4		0.36
MutPred		0.47		.;Loss of MoRF binding (P = 0.1028);.;Loss of MoRF binding (P = 0.1028);.;
MVP		0.95
MPC		1.5
ClinPred		0.62	D
GERP RS		4.4
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.67
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs797044474; hg19: chrX-53245299;