X-53217264-C-G

Variant names:

• chrX-53217264-C-G
• rs201805773
• NM_004187.5:c.536G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000375401.8(KDM5C):​c.536G>C​(p.Arg179Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R179H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: KDM5C ENST00000375401.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.20
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• syndromic X-linked intellectual disability Claes-Jensen type

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• X-linked syndromic intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22631428).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000375401.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM5C	NM_004187.5	MANE Select	c.536G>C	p.Arg179Pro	missense	Exon 5 of 26	NP_004178.2
	KDM5C	NM_001282622.3		c.533G>C	p.Arg178Pro	missense	Exon 5 of 26	NP_001269551.1
	KDM5C	NM_001353978.3		c.536G>C	p.Arg179Pro	missense	Exon 5 of 26	NP_001340907.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM5C	ENST00000375401.8	TSL:1 MANE Select	c.536G>C	p.Arg179Pro	missense	Exon 5 of 26	ENSP00000364550.4
	KDM5C	ENST00000404049.7	TSL:1	c.533G>C	p.Arg178Pro	missense	Exon 5 of 26	ENSP00000385394.3
	KDM5C	ENST00000375379.7	TSL:5	c.536G>C	p.Arg179Pro	missense	Exon 5 of 26	ENSP00000364528.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.078	T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.81	L
PhyloP100		2.2
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.21
Sift	Benign	0.60	T
Sift4G	Benign	0.36	T
Polyphen		0.0	B
Vest4		0.59
MutPred		0.62		Gain of catalytic residue at N177 (P = 0.0569)
MVP		0.83
MPC		2.1
ClinPred		0.34	T
GERP RS		5.3
Varity_R		0.33
gMVP		0.82
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs201805773; hg19: chrX-53246446;