NM_004187.5:c.4675C>A

Variant names:

• chrX-53192975-G-T
• rs1463790897
• NM_004187.5:c.4675C>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_004187.5(KDM5C):​c.4675C>A​(p.Gln1559Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000333 in 1,051,433 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.000033 (0 hom. 12 hem.)
• Consequence: KDM5C NM_004187.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 2.28

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PP2: Missense variant in the KDM5C gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 36 curated pathogenic missense variants (we use a threshold of 10). The gene has 40 curated benign missense variants. Gene score misZ: 5.1452 (above the threshold of 3.09). GenCC associations: The gene is linked to X-linked syndromic intellectual disability, syndromic X-linked intellectual disability Claes-Jensen type.
• BP4: Computational evidence support a benign effect (MetaRNN=0.1894806).
• BP6: Variant X-53192975-G-T is Benign according to our data. Variant chrX-53192975-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1211975.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS2: High Hemizygotes in GnomAdExome4 at 12 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDM5C	NM_004187.5	c.4675C>A	p.Gln1559Lys	missense_variant	Exon 26 of 26	ENST00000375401.8	NP_004178.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDM5C	ENST00000375401.8	c.4675C>A	p.Gln1559Lys	missense_variant	Exon 26 of 26	1	NM_004187.5	ENSP00000364550.4

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome AF: 0.0000333 AC: 35 AN: 1051433 Hom.: 0 Cov.: 33 AF XY: 0.0000357 AC XY: 12 AN XY: 335999

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000392

Gnomad4 OTH exome AF: 0.0000685

GnomAD4 genome Cov.: 20

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KDM5C: BS2 -

Mar 05, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spastic paraplegia Uncertain:1

Nov 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 1559 of the KDM5C protein (p.Gln1559Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KDM5C-related conditions. ClinVar contains an entry for this variant (Variation ID: 1211975). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt KDM5C protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.0083	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	20
DANN	Benign	0.93
DEOGEN2	Benign	0.092	T;.;.;.
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	0.46	N;.;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.18	N;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.28	T;T;T;T
Sift4G	Uncertain	0.054	T;T;T;T
Polyphen		0.049	B;.;.;.
Vest4		0.29
MVP		0.85
MPC		0.70
ClinPred		0.43	T
GERP RS		3.7
Varity_R		0.26
gMVP		0.63

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

Publications

LitVar

Other links and lift over

dbSNP: rs1463790897; hg19: chrX-53222157;