rs143955805

Positions:

• chrX-53196844-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004187.5(KDM5C):​c.2823A>G​(p.Ser941=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,207,911 control chromosomes in the GnomAD database, including 2 homozygotes. There are 477 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., 53 hem., cov: 25)
  • Exomes 𝑓: 0.0012 (1 hom. 424 hem.)
• Consequence: KDM5C NM_004187.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.00400

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant X-53196844-T-C is Benign according to our data. Variant chrX-53196844-T-C is described in ClinVar as [Benign]. Clinvar id is 211248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-53196844-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.004 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00138 (157/113510) while in subpopulation AMR AF= 0.0034 (37/10880). AF 95% confidence interval is 0.00254. There are 1 homozygotes in gnomad4. There are 53 alleles in male gnomad4 subpopulation. Median coverage is 25. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 53 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KDM5C	NM_004187.5	c.2823A>G	p.Ser941=	synonymous_variant	19/26	ENST00000375401.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KDM5C	ENST00000375401.8	c.2823A>G	p.Ser941=	synonymous_variant	19/26	1	NM_004187.5	P5

Frequencies

GnomAD3 genomes AF: 0.00138 AC: 157 AN: 113459 Hom.: 1 Cov.: 25 AF XY: 0.00149 AC XY: 53 AN XY: 35593

Gnomad AFR AF: 0.000352

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00639

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000702

Gnomad FIN AF: 0.00251

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00133

Gnomad OTH AF: 0.00195

GnomAD3 exomes AF: 0.00131 AC: 224 AN: 171337 Hom.: 0 AF XY: 0.00145 AC XY: 84 AN XY: 57875

Gnomad AFR exome AF: 0.000163

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00482

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000335

Gnomad FIN exome AF: 0.00300

Gnomad NFE exome AF: 0.00124

Gnomad OTH exome AF: 0.00330

GnomAD4 exome AF: 0.00119 AC: 1306 AN: 1094401 Hom.: 1 Cov.: 32 AF XY: 0.00118 AC XY: 424 AN XY: 360161

Gnomad4 AFR exome AF: 0.0000760

Gnomad4 AMR exome AF: 0.00135

Gnomad4 ASJ exome AF: 0.00638

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000355

Gnomad4 FIN exome AF: 0.00281

Gnomad4 NFE exome AF: 0.00112

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.00138 AC: 157 AN: 113510 Hom.: 1 Cov.: 25 AF XY: 0.00149 AC XY: 53 AN XY: 35654

Gnomad4 AFR AF: 0.000351

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.00639

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000703

Gnomad4 FIN AF: 0.00251

Gnomad4 NFE AF: 0.00133

Gnomad4 OTH AF: 0.00193

Alfa AF: 0.00171 Hom.: 13

Bravo AF: 0.00151

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 24, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 02, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 02, 2019

- -

KDM5C-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 24, 2019

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

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	9.6
DANN	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs143955805; hg19: chrX-53226026; COSMIC: COSV104428173; COSMIC: COSV104428173;