X-53193087-C-A

Position:

chrX-53193087-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_004187.5(KDM5C):c.4563G>T(p.Glu1521Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000414 in 1,207,198 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 20)

Exomes 𝑓: 0.0000018 ( 0 hom. 1 hem. )

Consequence

KDM5C
NM_004187.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.10

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:

KDM5C (HGNC:):

KDM5C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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=0.073717475).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDM5C	NM_004187.5 linkuse as main transcript	c.4563G>T	p.Glu1521Asp	missense_variant	26/26	ENST00000375401.8	NP_004178.2	P41229-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KDM5C	ENST00000375401.8 linkuse as main transcript	c.4563G>T	p.Glu1521Asp	missense_variant	26/26	1	NM_004187.5	ENSP00000364550.4		P41229-1

Frequencies

GnomAD3 genomes

AF:

0.0000272

AC:

AN:

110180

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32426

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000285

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:

0.00000563

AC:

AN:

177598

Hom.:

AF XY:

0.00

AC XY:

AN XY:

63504

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000127

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000182

AC:

AN:

1097018

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

362500

show subpopulations

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:

0.00000238

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000272

AC:

AN:

110180

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32426

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000285

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

Bravo

AF:

0.0000529

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Spastic paraplegia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 1521 of the KDM5C protein (p.Glu1521Asp). This variant is present in population databases (rs782274958, gnomAD 0.001%). This variant has not been reported in the literature in individuals affected with KDM5C-related conditions. ClinVar contains an entry for this variant (Variation ID: 567330). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KDM5C protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

KDM5C-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 01, 2022

The KDM5C c.4563G>T variant is predicted to result in the amino acid substitution p.Glu1521Asp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0013% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/X-53222269-C-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

T;.;.;.

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.87

D;D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.074

T;T;T;T

MetaSVM

Benign

-0.73

MutationAssessor

Benign

0.81

L;.;.;.

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.16

N;N;N;N

REVEL

Benign

0.19

Sift

Benign

0.21

T;T;T;T

Sift4G

Benign

0.29

T;T;T;T

Polyphen

0.039

B;.;.;.

Vest4

0.091

MutPred

0.034

Gain of glycosylation at S1518 (P = 0.2271);.;.;.;

MVP

0.47

MPC

0.55

ClinPred

0.084

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.087

gMVP

0.41

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