NM_004187.5:c.4498G>A

Variant names:

• chrX-53193152-C-T
• rs782774569
• NM_004187.5:c.4498G>A

Variant summary

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

The NM_004187.5(KDM5C):​c.4498G>A​(p.Glu1500Lys) 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. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 21)
• Consequence: KDM5C NM_004187.5 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 3.42
• Publications: 2 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, Labcorp Genetics (formerly Invitae), G2P, 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=0.13550088).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004187.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM5C	NM_004187.5	MANE Select	c.4498G>A	p.Glu1500Lys	missense	Exon 26 of 26	NP_004178.2	P41229-1
	KDM5C	NM_001282622.3		c.4495G>A	p.Glu1499Lys	missense	Exon 26 of 26	NP_001269551.1	P41229-5
	KDM5C	NM_001353978.3		c.4489G>A	p.Glu1497Lys	missense	Exon 26 of 26	NP_001340907.1	P41229-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM5C	ENST00000375401.8	TSL:1 MANE Select	c.4498G>A	p.Glu1500Lys	missense	Exon 26 of 26	ENSP00000364550.4	P41229-1
	KDM5C	ENST00000404049.7	TSL:1	c.4495G>A	p.Glu1499Lys	missense	Exon 26 of 26	ENSP00000385394.3	P41229-5
	KDM5C	ENST00000935430.1		c.4600G>A	p.Glu1534Lys	missense	Exon 27 of 27	ENSP00000605489.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD2 exomes AF: 0.00000549 AC: 1 AN: 182255 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 21

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.55	N
PhyloP100		3.4
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	0.68	N
REVEL	Benign	0.13
Sift	Benign	0.34	T
Sift4G	Benign	0.60	T
Polyphen		0.42	B
Vest4		0.22
MutPred		0.19		Gain of ubiquitination at E1500 (P = 0.0042)
MVP		0.55
MPC		0.71
ClinPred		0.19	T
GERP RS		2.8
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		4.0
Varity_R		0.17
gMVP		0.61
Mutation Taster		=95/5	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: rs782774569; hg19: chrX-53222334;