X-53196882-G-C

Variant names:

• chrX-53196882-G-C
• rs782405999
• NM_004187.5:c.2785C>G

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.2785C>G​(p.Arg929Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000025 in 1,200,844 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000088 (0 hom., 0 hem., cov: 24)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: KDM5C NM_004187.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.26
• Publications: 4 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=0.19370577).

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.2785C>G	p.Arg929Gly	missense	Exon 19 of 26	NP_004178.2	P41229-1
	KDM5C	NM_001282622.3		c.2782C>G	p.Arg928Gly	missense	Exon 19 of 26	NP_001269551.1	P41229-5
	KDM5C	NM_001353978.3		c.2785C>G	p.Arg929Gly	missense	Exon 19 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.2785C>G	p.Arg929Gly	missense	Exon 19 of 26	ENSP00000364550.4	P41229-1
	KDM5C	ENST00000404049.7	TSL:1	c.2782C>G	p.Arg928Gly	missense	Exon 19 of 26	ENSP00000385394.3	P41229-5
	KDM5C	ENST00000935430.1		c.2887C>G	p.Arg963Gly	missense	Exon 20 of 27	ENSP00000605489.1

Frequencies

GnomAD3 genomes AF: 0.00000883 AC: 1 AN: 113187 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: 0.00

Gnomad SAS AF: 0.000356

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000639 AC: 1 AN: 156382 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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000184 AC: 2 AN: 1087605 Hom.: 0 Cov.: 32 AF XY: 0.00000282 AC XY: 1 AN XY: 355201

African (AFR) AF: 0.00 AC: 0 AN: 26169

American (AMR) AF: 0.00 AC: 0 AN: 33818

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19177

East Asian (EAS) AF: 0.00 AC: 0 AN: 29575

South Asian (SAS) AF: 0.0000189 AC: 1 AN: 52785

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39603

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4037

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 836799

Other (OTH) AF: 0.00 AC: 0 AN: 45642

GnomAD4 genome AF: 0.00000883 AC: 1 AN: 113239 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 35389

African (AFR) AF: 0.00 AC: 0 AN: 31269

American (AMR) AF: 0.00 AC: 0 AN: 10849

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3575

South Asian (SAS) AF: 0.000357 AC: 1 AN: 2800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53327

Other (OTH) AF: 0.00 AC: 0 AN: 1544

ExAC AF: 0.00000829 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Syndromic X-linked intellectual disability Claes-Jensen type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.3
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.086
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.011	D
Polyphen		0.26	B
Vest4		0.33
MutPred		0.61		Loss of MoRF binding (P = 0.0144)
MVP		0.26
MPC		0.78
ClinPred		0.81	D
GERP RS		4.4
Varity_R		0.43
gMVP		0.68
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs782405999; hg19: chrX-53226064;