rs148661902

Positions:

chrX-53196941-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_004187.5(KDM5C):c.2726G>A(p.Arg909Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000619 in 1,196,158 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 17 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R909W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., 5 hem., cov: 24)

Exomes 𝑓: 0.000030 ( 0 hom. 12 hem. )

Consequence

KDM5C
NM_004187.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 0.165

Variant links:

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]

KDM5C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

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). GenCC has associacion of gene with X-linked syndromic intellectual disability, syndromic X-linked intellectual disability Claes-Jensen type.

BP4

Computational evidence support a benign effect (MetaRNN=0.011139333).

BP6

Variant X-53196941-C-T is Benign according to our data. Variant chrX-53196941-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211247.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000372 (42/112831) while in subpopulation AFR AF= 0.00132 (41/31097). AF 95% confidence interval is 0.000999. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KDM5C	NM_004187.5 linkuse as main transcript	c.2726G>A	p.Arg909Gln	missense_variant	19/26	ENST00000375401.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KDM5C	ENST00000375401.8 linkuse as main transcript	c.2726G>A	p.Arg909Gln	missense_variant	19/26	1	NM_004187.5	P5	P41229-1

Frequencies

GnomAD3 genomes

AF:

0.000372

AC:

AN:

112831

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

AN XY:

34995

show subpopulations

Gnomad AFR

AF:

0.00132

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000926

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000865

AC:

AN:

150376

Hom.:

AF XY:

0.0000655

AC XY:

AN XY:

45780

show subpopulations

Gnomad AFR exome

AF:

0.00112

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000255

GnomAD4 exome

AF:

0.0000295

AC:

AN:

1083327

Hom.:

Cov.:

AF XY:

0.0000340

AC XY:

AN XY:

352575

show subpopulations

Gnomad4 AFR exome

AF:

0.00107

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:

0.00000240

Gnomad4 OTH exome

AF:

0.0000440

GnomAD4 genome

AF:

0.000372

AC:

AN:

112831

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

AN XY:

34995

show subpopulations

Gnomad4 AFR

AF:

0.00132

Gnomad4 AMR

AF:

0.0000926

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000217

Hom.:

Bravo

AF:

0.000321

ESP6500AA

AF:

0.00131

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000831

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 06, 2014

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 20, 2017

The R909Q variant in the KDM5C gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R909Q variant is observed in 8/4,555 (0.17%) alleles from individuals of African background in the ExAC dataset (Lek et al., 2016). The R909Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R909Q as a variant of uncertain significance. -

Spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 16, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.96

CADD

Benign

2.6

DANN

Benign

0.90

DEOGEN2

Benign

0.079

.;T;.;.;.

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.72

T;T;T;T;T

M_CAP

Benign

0.0094

MetaRNN

Benign

0.011

T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.2

.;N;.;N;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

0.76

N;N;N;N;N

REVEL

Benign

0.10

Sift

Benign

0.66

T;T;T;T;T

Sift4G

Benign

0.59

T;T;T;T;T

Polyphen

0.0

.;B;.;.;.

Vest4

0.084

MVP

0.24

MPC

0.63

ClinPred

0.0085

GERP RS

-6.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.027

gMVP

0.18

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over