rs398124111

Positions:

• chrX-53197882-A-AAGT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_004187.5(KDM5C):​c.2517-9_2517-7dupACT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.014 in 1,161,391 control chromosomes in the GnomAD database, including 83 homozygotes. There are 5,002 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (2 hom., 232 hem., cov: 22)
  • Exomes 𝑓: 0.014 (81 hom. 4770 hem.)
• Consequence: KDM5C NM_004187.5 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.48

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 Benign. Variant got -16 ACMG points.

• BP6: Variant X-53197882-A-AAGT is Benign according to our data. Variant chrX-53197882-A-AAGT is described in ClinVar as [Likely_benign]. Clinvar id is 94874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00905 (1011/111747) while in subpopulation NFE AF= 0.0152 (807/53084). AF 95% confidence interval is 0.0143. There are 2 homozygotes in gnomad4. There are 232 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDM5C	NM_004187.5	c.2517-9_2517-7dupACT		splice_region_variant, intron_variant		ENST00000375401.8	NP_004178.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KDM5C	ENST00000375401.8	c.2517-7_2517-6insACT		splice_region_variant, intron_variant		1	NM_004187.5	ENSP00000364550.4

Frequencies

GnomAD3 genomes AF: 0.00905 AC: 1011 AN: 111695 Hom.: 2 Cov.: 22 AF XY: 0.00685 AC XY: 232 AN XY: 33865

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.00735

Gnomad AMR AF: 0.00493

Gnomad ASJ AF: 0.0106

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00148

Gnomad FIN AF: 0.00725

Gnomad MID AF: 0.00837

Gnomad NFE AF: 0.0152

Gnomad OTH AF: 0.00801

GnomAD3 exomes AF: 0.00994 AC: 1325 AN: 133366 Hom.: 6 AF XY: 0.00963 AC XY: 402 AN XY: 41726

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00792

Gnomad ASJ exome AF: 0.0157

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00370

Gnomad FIN exome AF: 0.00873

Gnomad NFE exome AF: 0.0148

Gnomad OTH exome AF: 0.0165

GnomAD4 exome AF: 0.0145 AC: 15211 AN: 1049644 Hom.: 81 Cov.: 26 AF XY: 0.0145 AC XY: 4770 AN XY: 328228

Gnomad4 AFR exome AF: 0.00202

Gnomad4 AMR exome AF: 0.00765

Gnomad4 ASJ exome AF: 0.0137

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00438

Gnomad4 FIN exome AF: 0.00891

Gnomad4 NFE exome AF: 0.0167

Gnomad4 OTH exome AF: 0.0120

GnomAD4 genome AF: 0.00905 AC: 1011 AN: 111747 Hom.: 2 Cov.: 22 AF XY: 0.00684 AC XY: 232 AN XY: 33927

Gnomad4 AFR AF: 0.00185

Gnomad4 AMR AF: 0.00493

Gnomad4 ASJ AF: 0.0106

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00149

Gnomad4 FIN AF: 0.00725

Gnomad4 NFE AF: 0.0152

Gnomad4 OTH AF: 0.00791

Alfa AF: 0.0107 Hom.: 78

Bravo AF: 0.00895

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 24, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Eurofins Ntd Llc (ga)	Aug 30, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 20, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 23, 2019	- -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2014

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

KDM5C-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 20, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs398124111; hg19: chrX-53227064;