X-53193084-G-T

Position:

chrX-53193084-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_004187.5(KDM5C):c.4566C>A(p.Asn1522Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000058 in 1,207,054 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 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 0.0000091 ( 0 hom., 0 hem., cov: 21)

Exomes 𝑓: 0.0000055 ( 0 hom. 4 hem. )

Consequence

KDM5C
NM_004187.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 1.50

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 Likely_benign. Variant got -5 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=0.19687027).

BS2

High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDM5C	NM_004187.5 linkuse as main transcript	c.4566C>A	p.Asn1522Lys	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.4566C>A	p.Asn1522Lys	missense_variant	26/26	1	NM_004187.5	ENSP00000364550.4		P41229-1

Frequencies

GnomAD3 genomes

AF:

0.00000908

AC:

AN:

110088

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32364

show subpopulations

Gnomad AFR

AF:

0.0000331

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1096966

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

362444

show subpopulations

Gnomad4 AFR exome

AF:

0.000114

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:

0.00

Gnomad4 OTH exome

AF:

0.0000435

GnomAD4 genome

AF:

0.00000908

AC:

AN:

110088

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32364

show subpopulations

Gnomad4 AFR

AF:

0.0000331

Gnomad4 AMR

AF:

0.00

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:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

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

Aug 30, 2023

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 1522 of the KDM5C protein (p.Asn1522Lys). 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. 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. ClinVar contains an entry for this variant (Variation ID: 435565). This variant has not been reported in the literature in individuals affected with KDM5C-related conditions. This variant is not present in population databases (gnomAD no frequency). -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 08, 2016

- -

Syndromic X-linked intellectual disability Claes-Jensen type

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 09, 2020

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Jul 29, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;.;.;.

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.92

D;D;D;D

M_CAP

Pathogenic

0.36

MetaRNN

Benign

0.20

T;T;T;T

MetaSVM

Benign

-0.37

MutationAssessor

Benign

0.90

L;.;.;.

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.56

N;N;N;N

REVEL

Benign

0.18

Sift

Uncertain

0.024

D;D;D;D

Sift4G

Benign

0.28

T;T;T;T

Polyphen

0.0080

B;.;.;.

Vest4

0.092

MutPred

0.15

Gain of ubiquitination at N1522 (P = 0);.;.;.;

MVP

0.66

MPC

0.64

ClinPred

0.63

GERP RS

3.7

Varity_R

0.21

gMVP

0.29

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