rs587780371

Variant names:

• chrX-53196049-T-C
• rs587780371
• NM_004187.5:c.2987A>G
• KDM5C p.Lys996Arg

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004187.5(KDM5C):​c.2987A>G​(p.Lys996Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,097,795 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.000011 (0 hom. 2 hem.)
• Consequence: KDM5C NM_004187.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.00
• 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: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• X-linked syndromic intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09474051).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

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.2987A>G	p.Lys996Arg	missense	Exon 20 of 26	NP_004178.2	P41229-1
	KDM5C	NM_001282622.3		c.2984A>G	p.Lys995Arg	missense	Exon 20 of 26	NP_001269551.1	P41229-5
	KDM5C	NM_001353978.3		c.2987A>G	p.Lys996Arg	missense	Exon 20 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.2987A>G	p.Lys996Arg	missense	Exon 20 of 26	ENSP00000364550.4	P41229-1
	KDM5C	ENST00000404049.7	TSL:1	c.2984A>G	p.Lys995Arg	missense	Exon 20 of 26	ENSP00000385394.3	P41229-5
	KDM5C	ENST00000935430.1		c.3089A>G	p.Lys1030Arg	missense	Exon 21 of 27	ENSP00000605489.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.00000549 AC: 1 AN: 182106 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: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 12 AN: 1097795 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 2 AN XY: 363161

African (AFR) AF: 0.00 AC: 0 AN: 26395

American (AMR) AF: 0.00 AC: 0 AN: 35182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19378

East Asian (EAS) AF: 0.00 AC: 0 AN: 30194

South Asian (SAS) AF: 0.00 AC: 0 AN: 54081

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40495

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4127

European-Non Finnish (NFE) AF: 0.0000131 AC: 11 AN: 841874

Other (OTH) AF: 0.0000217 AC: 1 AN: 46069

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	Benign	0.14
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Uncertain	23
DANN	Benign	0.94
DEOGEN2	Benign	0.068	T
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.095	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.0
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.62
Mutation Taster		=80/20	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs587780371;

hg19: chrX-53225231;