NM_004187.5:c.4597A>C

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_004187.5(KDM5C):c.4597A>C(p.Thr1533Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000898 in 1,203,148 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 25 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., 13 hem., cov: 20)

Exomes 𝑓: 0.000050 ( 0 hom. 12 hem. )

Consequence

KDM5C
NM_004187.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: 0.273

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in the KDM5C gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 36 curated pathogenic missense variants (we use a threshold of 10). The gene has 40 curated benign missense variants. Gene score misZ: 5.1452 (above the threshold of 3.09). GenCC associations: The gene is linked to X-linked syndromic intellectual disability, syndromic X-linked intellectual disability Claes-Jensen type.

BP4

Computational evidence support a benign effect (MetaRNN=0.020959556).

BP6

Variant X-53193053-T-G is Benign according to our data. Variant chrX-53193053-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 134592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000485 (53/109379) while in subpopulation AFR AF= 0.00167 (50/29950). AF 95% confidence interval is 0.0013. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 20. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 13 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDM5C	NM_004187.5 link	c.4597A>C	p.Thr1533Pro	missense_variant	Exon 26 of 26	ENST00000375401.8	NP_004178.2	P41229-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDM5C	ENST00000375401.8 link	c.4597A>C	p.Thr1533Pro	missense_variant	Exon 26 of 26	1	NM_004187.5	ENSP00000364550.4		P41229-1

Frequencies

GnomAD3 genomes

AF:

0.000485

AC:

AN:

109379

Hom.:

Cov.:

AF XY:

0.000409

AC XY:

AN XY:

31755

show subpopulations

Gnomad AFR

AF:

0.00167

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:

0.0000191

Gnomad OTH

AF:

0.00135

GnomAD3 exomes

AF:

0.000140

AC:

AN:

171750

Hom.:

AF XY:

0.0000687

AC XY:

AN XY:

58202

show subpopulations

Gnomad AFR exome

AF:

0.00176

Gnomad AMR exome

AF:

0.0000749

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:

0.00

GnomAD4 exome

AF:

0.0000503

AC:

AN:

1093769

Hom.:

Cov.:

AF XY:

0.0000334

AC XY:

AN XY:

359643

show subpopulations

Gnomad4 AFR exome

AF:

0.00186

Gnomad4 AMR exome

AF:

0.0000859

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:

0.00000119

Gnomad4 OTH exome

AF:

0.0000436

GnomAD4 genome

AF:

0.000485

AC:

AN:

109379

Hom.:

Cov.:

AF XY:

0.000409

AC XY:

AN XY:

31755

show subpopulations

Gnomad4 AFR

AF:

0.00167

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:

0.0000191

Gnomad4 OTH

AF:

0.00135

Alfa

AF:

0.0000764

Hom.:

Bravo

AF:

0.000657

ESP6500AA

AF:

0.00156

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000107

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Spastic paraplegia

Benign:1

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Oct 02, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided

Benign:1

Oct 26, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.50

CADD

Benign

5.9

DANN

Benign

0.89

DEOGEN2

Benign

0.082

T;.;.;.

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.73

T;T;T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.021

T;T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.34

N;.;.;.

PrimateAI

Uncertain

0.56

PROVEAN

Benign

0.15

N;N;N;N

REVEL

Benign

0.22

Sift

Benign

0.20

T;T;T;T

Sift4G

Benign

0.12

T;T;T;T

Polyphen

0.0

B;.;.;.

Vest4

0.20

MVP

0.23

MPC

0.71

ClinPred

0.0016

GERP RS

-0.57

Varity_R

0.066

gMVP

0.37

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