rs797045640

Positions:

• chrX-53198977-C-G
• chrX-53198977-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_004187.5(KDM5C):​c.2243G>C​(p.Arg748Pro) variant causes a missense, splice region change. 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 predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: KDM5C NM_004187.5 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.72

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]

KDM5C (HGNC:):

ACMG classification

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). GenCC has associacion of gene with X-linked syndromic intellectual disability, syndromic X-linked intellectual disability Claes-Jensen type.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDM5C	NM_004187.5	c.2243G>C	p.Arg748Pro	missense_variant, splice_region_variant	15/26	ENST00000375401.8	NP_004178.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KDM5C	ENST00000375401.8	c.2243G>C	p.Arg748Pro	missense_variant, splice_region_variant	15/26	1	NM_004187.5	ENSP00000364550.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 21, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	.;D;.;.;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.7	.;M;.;M;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-4.8	D;D;D;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.012	D;D;D;D;D
Sift4G	Uncertain	0.031	D;D;D;D;D
Polyphen		1.0	.;D;.;.;.
Vest4		0.77
MutPred		0.80		.;Gain of glycosylation at R748 (P = 0.0398);.;Gain of glycosylation at R748 (P = 0.0398);.;
MVP		0.97
MPC		3.0
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.99
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.050		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: rs797045640; hg19: chrX-53228159;