rs782205045

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_004187.5(KDM5C):c.3442G>A(p.Val1148Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000128 in 1,097,585 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.000013 ( 0 hom. 5 hem. )

Consequence

KDM5C
NM_004187.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.80

Publications

0 publications found

Variant links:

COSMIC-nc: COSV64765058

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 Gene-Disease associations (from GenCC):

syndromic X-linked intellectual disability Claes-Jensen type
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
X-linked syndromic intellectual disability
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen

KDM5C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13291487).

BP6

Variant X-53194735-C-T is Benign according to our data. Variant chrX-53194735-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 522629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAdExome4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDM5C	NM_004187.5 link	c.3442G>A	p.Val1148Met	missense_variant	Exon 23 of 26	ENST00000375401.8	NP_004178.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDM5C	ENST00000375401.8 link	c.3442G>A	p.Val1148Met	missense_variant	Exon 23 of 26	1	NM_004187.5	ENSP00000364550.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000111

AC:

AN:

180221

AF XY:

0.0000152

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000126

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000128

AC:

AN:

1097585

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

363009

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26376

American (AMR)

AF:

0.00

AC:

AN:

35171

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19374

East Asian (EAS)

AF:

0.0000662

AC:

AN:

30198

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54028

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40478

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3984

European-Non Finnish (NFE)

AF:

0.00000950

AC:

AN:

841926

Other (OTH)

AF:

0.0000651

AC:

AN:

46050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Spastic paraplegia

Benign:1

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Syndromic X-linked intellectual disability Claes-Jensen type

Benign:1

Oct 07, 2023

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.10

.;T;.;.;.

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.87

D;D;D;D;D

M_CAP

Benign

0.040

MetaRNN

Benign

0.13

T;T;T;T;T

MetaSVM

Benign

-0.65

MutationAssessor

Benign

-0.030

.;N;.;N;.

PhyloP100

1.8

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.56

N;N;N;N;N

REVEL

Benign

0.20

Sift

Benign

0.14

T;T;T;T;T

Sift4G

Benign

0.16

T;T;T;T;T

Polyphen

0.15

.;B;.;.;.

Vest4

0.26

MutPred

0.38

.;Gain of disorder (P = 0.0471);.;Gain of disorder (P = 0.0471);.;

MVP

0.70

MPC

0.56

ClinPred

0.31

GERP RS

3.9

Varity_R

0.14

gMVP

0.82

Mutation Taster

=92/8

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over