chrX-53198499-T-C

Variant names:

• chrX-53198499-T-C
• rs192633186
• NM_004187.5:c.2507A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000375401.8(KDM5C):​c.2507A>G​(p.Gln836Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 112,400 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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: 𝑓 0.000027 (0 hom., 0 hem., cov: 24)
• Consequence: KDM5C ENST00000375401.8 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 2.06
• 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, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• X-linked syndromic intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02560231).

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.2507A>G	p.Gln836Arg	missense	Exon 17 of 26	NP_004178.2
	KDM5C	NM_001282622.3		c.2504A>G	p.Gln835Arg	missense	Exon 17 of 26	NP_001269551.1
	KDM5C	NM_001353978.3		c.2507A>G	p.Gln836Arg	missense	Exon 17 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.2507A>G	p.Gln836Arg	missense	Exon 17 of 26	ENSP00000364550.4
	KDM5C	ENST00000404049.7	TSL:1	c.2504A>G	p.Gln835Arg	missense	Exon 17 of 26	ENSP00000385394.3
	KDM5C	ENST00000375379.7	TSL:5	c.2507A>G	p.Gln836Arg	missense	Exon 17 of 26	ENSP00000364528.3

Frequencies

GnomAD3 genomes AF: 0.0000267 AC: 3 AN: 112346 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000834

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000185 AC: 3 AN: 161892 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000238

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.0000267 AC: 3 AN: 112400 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34554

African (AFR) AF: 0.00 AC: 0 AN: 30956

American (AMR) AF: 0.00 AC: 0 AN: 10652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.000837 AC: 3 AN: 3585

South Asian (SAS) AF: 0.00 AC: 0 AN: 2709

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53254

Other (OTH) AF: 0.00 AC: 0 AN: 1525

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

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	0.070
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.094	T
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.1
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.11	N
REVEL	Benign	0.043
Sift	Benign	0.21	T
Sift4G	Benign	0.38	T
Polyphen		0.0010	B
Vest4		0.10
MVP		0.36
MPC		0.59
ClinPred		0.14	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.20
gMVP		0.43
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs192633186; hg19: chrX-53227681;