Genetic Variant KDM5C:c.*129C>A (chrX-53192838-G-T) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_001146702.2(KDM5C):c.4047-1C>A variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000509 in 981,910 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 19)

Exomes 𝑓: 0.0000051 ( 0 hom. 0 hem. )

Consequence

KDM5C
NM_001146702.2 splice_acceptor, intron

Scores

Splicing: ADA: 0.00006424

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.948

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

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

KDM5C links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001146702.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
KDM5C	NM_004187.5	MANE Select	c.*129C>A	3_prime_UTR	Exon 26 of 26	NP_004178.2	P41229-1
KDM5C	NM_001282622.3		c.*129C>A	3_prime_UTR	Exon 26 of 26	NP_001269551.1	P41229-5
KDM5C	NM_001353978.3		c.*129C>A	3_prime_UTR	Exon 26 of 26	NP_001340907.1	P41229-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
KDM5C	ENST00000375401.8	TSL:1 MANE Select	c.*129C>A	3_prime_UTR	Exon 26 of 26	ENSP00000364550.4	P41229-1
KDM5C	ENST00000404049.7	TSL:1	c.*129C>A	3_prime_UTR	Exon 26 of 26	ENSP00000385394.3	P41229-5
KDM5C	ENST00000935430.1		c.*129C>A	3_prime_UTR	Exon 27 of 27	ENSP00000605489.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000509

AC:

AN:

981910

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

290144

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

23629

American (AMR)

AF:

0.00

AC:

AN:

26211

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16988

East Asian (EAS)

AF:

0.00

AC:

AN:

26091

South Asian (SAS)

AF:

0.00

AC:

AN:

45392

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36752

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3058

European-Non Finnish (NFE)

AF:

0.00000656

AC:

AN:

762564

Other (OTH)

AF:

0.00

AC:

AN:

41225

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.84

CADD

Benign

4.4

(source)

DANN

Benign

0.81

FATHMM_MKL

Benign

0.49

PhyloP100

0.95

GERP RS

0.30

Mutation Taster

=77/23

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000064

dbscSNV1_RF

Benign

0.0080

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over