Genetic Variant KDM5C:p.Arg909Gln (chrX-53196941-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004187.5(KDM5C):c.2726G>A(p.Arg909Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000619 in 1,196,158 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 17 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R909W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., 5 hem., cov: 24)

Exomes 𝑓: 0.000030 ( 0 hom. 12 hem. )

Consequence

KDM5C
NM_004187.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 0.165

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, Labcorp Genetics (formerly Invitae), G2P, 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011139333).

BP6

Variant X-53196941-C-T is Benign according to our data. Variant chrX-53196941-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211247.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000372 (42/112831) while in subpopulation AFR AF = 0.00132 (41/31097). AF 95% confidence interval is 0.000999. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 5 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004187.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KDM5C	NM_004187.5	MANE Select	c.2726G>A	p.Arg909Gln	missense	Exon 19 of 26	NP_004178.2	P41229-1
KDM5C	NM_001282622.3		c.2723G>A	p.Arg908Gln	missense	Exon 19 of 26	NP_001269551.1	P41229-5
KDM5C	NM_001353978.3		c.2726G>A	p.Arg909Gln	missense	Exon 19 of 26	NP_001340907.1	P41229-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KDM5C	ENST00000375401.8	TSL:1 MANE Select	c.2726G>A	p.Arg909Gln	missense	Exon 19 of 26	ENSP00000364550.4	P41229-1
KDM5C	ENST00000404049.7	TSL:1	c.2723G>A	p.Arg908Gln	missense	Exon 19 of 26	ENSP00000385394.3	P41229-5
KDM5C	ENST00000935430.1		c.2828G>A	p.Arg943Gln	missense	Exon 20 of 27	ENSP00000605489.1

Frequencies

GnomAD3 genomes

AF:

0.000372

AC:

AN:

112831

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00132

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000926

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

GnomAD2 exomes

AF:

0.0000865

AC:

AN:

150376

AF XY:

0.0000655

show subpopulations

Gnomad AFR exome

AF:

0.00112

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:

0.000255

GnomAD4 exome

AF:

0.0000295

AC:

AN:

1083327

Hom.:

Cov.:

AF XY:

0.0000340

AC XY:

AN XY:

352575

show subpopulations

African (AFR)

AF:

0.00107

AC:

AN:

26079

American (AMR)

AF:

0.00

AC:

AN:

33492

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19067

East Asian (EAS)

AF:

0.00

AC:

AN:

29448

South Asian (SAS)

AF:

0.00

AC:

AN:

52181

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39488

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3764

European-Non Finnish (NFE)

AF:

0.00000240

AC:

AN:

834328

Other (OTH)

AF:

0.0000440

AC:

AN:

45480

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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

AF:

0.000372

AC:

AN:

112831

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

AN XY:

34995

show subpopulations

African (AFR)

AF:

0.00132

AC:

AN:

31097

American (AMR)

AF:

0.0000926

AC:

AN:

10802

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2647

East Asian (EAS)

AF:

0.00

AC:

AN:

3583

South Asian (SAS)

AF:

0.00

AC:

AN:

2762

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6272

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53229

Other (OTH)

AF:

0.00

AC:

AN:

1517

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000217

Hom.:

Bravo

AF:

0.000321

ESP6500AA

AF:

0.00131

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000831

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.96

CADD

Benign

2.6

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.079

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.72

M_CAP

Benign

0.0094

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.2

PhyloP100

0.17

PrimateAI

Benign

0.37

PROVEAN

Benign

0.76

REVEL

Benign

0.10

Sift

Benign

0.66

Sift4G

Benign

0.59

Polyphen

0.0

Vest4

0.084

MVP

0.24

MPC

0.63

ClinPred

0.0085

GERP RS

-6.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.027

gMVP

0.18

Mutation Taster

=100/0

polymorphism

(source)

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

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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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over