Genetic Variant KDM5C:c.*132C>A (chrX-53192835-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001146702.2(KDM5C):c.4049C>A(p.Pro1350His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000202 in 992,512 control chromosomes in the GnomAD database, including 1 homozygotes. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1350R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 19)

Exomes 𝑓: 0.0000020 ( 1 hom. 0 hem. )

Consequence

KDM5C
NM_001146702.2 missense, splice_region

Scores

Splicing: ADA: 0.00002683

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.885

Publications

2 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16978338).

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	HGVSp	Effect	Exon Rank	Protein
KDM5C	NM_004187.5	MANE Select	c.*132C>A		3_prime_UTR	Exon 26 of 26	NP_004178.2
KDM5C	NM_001146702.2		c.4049C>A	p.Pro1350His	missense splice_region	Exon 24 of 24	NP_001140174.1
KDM5C	NM_001282622.3		c.*132C>A		3_prime_UTR	Exon 26 of 26	NP_001269551.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KDM5C	ENST00000375401.8	TSL:1 MANE Select	c.*132C>A		3_prime_UTR	Exon 26 of 26	ENSP00000364550.4
KDM5C	ENST00000404049.7	TSL:1	c.*132C>A		3_prime_UTR	Exon 26 of 26	ENSP00000385394.3
KDM5C	ENST00000452825.7	TSL:5	c.4049C>A	p.Pro1350His	missense splice_region	Exon 24 of 24	ENSP00000445176.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000986

AC:

AN:

101407

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000156

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000202

AC:

AN:

992512

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

297710

show subpopulations

African (AFR)

AF:

0.0000839

AC:

AN:

23843

American (AMR)

AF:

0.00

AC:

AN:

26421

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17190

East Asian (EAS)

AF:

0.00

AC:

AN:

26319

South Asian (SAS)

AF:

0.00

AC:

AN:

46175

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36750

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3060

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

771078

Other (OTH)

AF:

0.00

AC:

AN:

41676

Age Distribution

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:

0.00000989

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.38

CADD

Benign

7.3

(source)

DANN

Benign

0.72

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.20

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.77

PhyloP100

0.89

PROVEAN

Benign

1.7

REVEL

Benign

0.15

Sift

Benign

0.41

Sift4G

Benign

0.57

Vest4

0.44

MutPred

0.49

Loss of loop (P = 0.0073)

MVP

0.68

ClinPred

0.038

GERP RS

0.98

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000027

dbscSNV1_RF

Benign

0.0020

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