rs61733871

chrX-53201956-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_004187.5(KDM5C):c.1764G>A(p.Gln588=) variant causes a synonymous change. The variant allele was found at a frequency of 0.00356 in 1,210,364 control chromosomes in the GnomAD database, including 10 homozygotes. There are 1,364 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., 84 hem., cov: 23)
  • Exomes 𝑓: 0.0036 (9 hom. 1280 hem.)
• Consequence: KDM5C NM_004187.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.17

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant X-53201956-C-T is Benign according to our data. Variant chrX-53201956-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 166871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-53201956-C-T is described in Lovd as [Benign]. Variant chrX-53201956-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00287 (322/112344) while in subpopulation NFE AF= 0.0049 (261/53263). AF 95% confidence interval is 0.00441. There are 1 homozygotes in gnomad4. There are 84 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 84 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KDM5C	NM_004187.5	c.1764G>A	p.Gln588=	synonymous_variant	13/26	ENST00000375401.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KDM5C	ENST00000375401.8	c.1764G>A	p.Gln588=	synonymous_variant	13/26	1	NM_004187.5	P5

Frequencies

GnomAD3 genomes AF: 0.00287 AC: 322 AN: 112291 Hom.: 1 Cov.: 23 AF XY: 0.00244 AC XY: 84 AN XY: 34433

Gnomad AFR AF: 0.000357

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00245

Gnomad ASJ AF: 0.00188

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000727

Gnomad FIN AF: 0.00180

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00490

Gnomad OTH AF: 0.00399

GnomAD3 exomes AF: 0.00266 AC: 489 AN: 183506 Hom.: 0 AF XY: 0.00290 AC XY: 197 AN XY: 67936

Gnomad AFR exome AF: 0.000608

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00120

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00126

Gnomad FIN exome AF: 0.00119

Gnomad NFE exome AF: 0.00461

Gnomad OTH exome AF: 0.00265

GnomAD4 exome AF: 0.00363 AC: 3989 AN: 1098020 Hom.: 9 Cov.: 30 AF XY: 0.00352 AC XY: 1280 AN XY: 363378

Gnomad4 AFR exome AF: 0.000493

Gnomad4 AMR exome AF: 0.00128

Gnomad4 ASJ exome AF: 0.00129

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00135

Gnomad4 FIN exome AF: 0.00217

Gnomad4 NFE exome AF: 0.00431

Gnomad4 OTH exome AF: 0.00250

GnomAD4 genome AF: 0.00287 AC: 322 AN: 112344 Hom.: 1 Cov.: 23 AF XY: 0.00244 AC XY: 84 AN XY: 34496

Gnomad4 AFR AF: 0.000356

Gnomad4 AMR AF: 0.00245

Gnomad4 ASJ AF: 0.00188

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000729

Gnomad4 FIN AF: 0.00180

Gnomad4 NFE AF: 0.00490

Gnomad4 OTH AF: 0.00394

Alfa AF: 0.00447 Hom.: 35

Bravo AF: 0.00268

EpiCase AF: 0.00311

EpiControl AF: 0.00356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 24, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 04, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2019	This variant is associated with the following publications: (PMID: 19377476, 24583395) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2016

This alteration is classified as likely 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, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 19, 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	-0.38
Cadd	Benign	6.4
Dann	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61733871; hg19: chrX-53231138; COSMIC: COSV64765425; COSMIC: COSV64765425;