rs782405999

chrX-53196882-G-AchrX-53196882-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004187.5(KDM5C):c.2785C>T(p.Arg929Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000919 in 1,087,605 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: KDM5C NM_004187.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.26

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-53196882-G-A is Pathogenic according to our data. Variant chrX-53196882-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 421004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KDM5C	NM_004187.5	c.2785C>T	p.Arg929Ter	stop_gained	19/26	ENST00000375401.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KDM5C	ENST00000375401.8	c.2785C>T	p.Arg929Ter	stop_gained	19/26	1	NM_004187.5	P5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.19e-7 AC: 1 AN: 1087605 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 355201

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: 0.00000120

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2017

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 28, 2022

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.46
Cadd	Pathogenic	35
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.84	D
MutationTaster	Benign	1.0	A;A;A;A;A
Vest4		0.91
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs782405999; hg19: chrX-53226064; COSMIC: COSV64765756; COSMIC: COSV64765756;