rs199422239

Positions:

• chrX-53218398-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_004187.5(KDM5C):​c.229G>A​(p.Ala77Thr) variant causes a missense, splice region 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. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: KDM5C NM_004187.5 missense, splice_region
• Scores: Splicing: ADA: 0.9602
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.84

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_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KDM5C. . Gene score misZ: 5.1452 (greater than the threshold 3.09). The gene has 36 curated pathogenic missense variants (we use a threshold of 10). The gene has 40 curated benign missense variants. GenCC has associacion of the gene with X-linked syndromic intellectual disability, syndromic X-linked intellectual disability Claes-Jensen type.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.842
• PP5: Variant X-53218398-C-T is Pathogenic according to our data. Variant chrX-53218398-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9778.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDM5C	NM_004187.5	c.229G>A	p.Ala77Thr	missense_variant, splice_region_variant	3/26	ENST00000375401.8	NP_004178.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KDM5C	ENST00000375401.8	c.229G>A	p.Ala77Thr	missense_variant, splice_region_variant	3/26	1	NM_004187.5	ENSP00000364550.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 2016

The p.A77T variant (also known as c.229G>A) is located in coding exon 3 of the KDM5C gene. This alteration results from a G to A substitution at nucleotide position 229. The alanine at codon 77 is replaced by threonine, an amino acid with similar properties. This change occurs in the first base pair of coding exon 3. This alteration was observed to track with disease in one family with seven affected individuals, three males and four females with skewed X-inactivation, and was not detected in 2 unaffected females; clinical features in this family included intellectual disability, short stature, strabismus, broad hands, and hyperreflexia (Abidi FE et al. J Med Genet. 2008; 45(12):787-93). A computational analysis found this alteration, which is located in the ARID domain, did not affect the DNA binding of this domain and authors suggest the mechanism of disease is not related to DNA binding (Peng et al. Int J Mol Sci. 2015;16(11):27270-87). This variant was previously reported in the SNPDatabase as rs199422239. This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), 1000 Genomes Project and ExAC. In the ESP, this variant was not observed in 6,503 samples with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Syndromic X-linked intellectual disability Claes-Jensen type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Uncertain	2.8	M;M;M
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.4	D;D;D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.50
MutPred		0.81		Loss of ubiquitination at K82 (P = 0.0818);Loss of ubiquitination at K82 (P = 0.0818);Loss of ubiquitination at K82 (P = 0.0818);
MVP		0.89
MPC		2.6
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Benign	0.66
SpliceAI score (max)		0.060		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: rs199422239; hg19: chrX-53247580;