chrX-53220843-A-G

Variant names:

• chrX-53220843-A-G
• rs1057520198
• NM_004187.5:c.224T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_004187.5(KDM5C):​c.224T>C​(p.Leu75Pro) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: KDM5C NM_004187.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.29
• 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, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• X-linked syndromic intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956
• PP5: Variant X-53220843-A-G is Pathogenic according to our data. Variant chrX-53220843-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 377331.Status of the report is criteria_provided_single_submitter, 1 stars.

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.224T>C	p.Leu75Pro	missense	Exon 2 of 26	NP_004178.2	P41229-1
	KDM5C	NM_001282622.3		c.224T>C	p.Leu75Pro	missense	Exon 2 of 26	NP_001269551.1	P41229-5
	KDM5C	NM_001353978.3		c.224T>C	p.Leu75Pro	missense	Exon 2 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.224T>C	p.Leu75Pro	missense	Exon 2 of 26	ENSP00000364550.4	P41229-1
	KDM5C	ENST00000404049.7	TSL:1	c.224T>C	p.Leu75Pro	missense	Exon 2 of 26	ENSP00000385394.3	P41229-5
	KDM5C	ENST00000935430.1		c.326T>C	p.Leu109Pro	missense	Exon 3 of 27	ENSP00000605489.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.60	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		9.3
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.97	D
Vest4		0.92
MutPred		0.74		Gain of disorder (P = 0.0182)
MVP		0.97
MPC		3.4
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.97
gMVP		0.99
Mutation Taster		=30/70	disease causing (ClinVar)

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: rs1057520198; hg19: chrX-53250025;