dbSNP rs35353912: KDM5C:p.Pro598Pro (chrX-53201926-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_004187.5(KDM5C):c.1794C>T(p.Pro598Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00306 in 1,210,529 control chromosomes in the GnomAD database, including 4 homozygotes. There are 1,171 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P598P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0021 ( 0 hom., 56 hem., cov: 23)

Exomes 𝑓: 0.0032 ( 4 hom. 1115 hem. )

Consequence

KDM5C
NM_004187.5 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 0.806

Publications

3 publications found

Variant links:

COSMIC-nc: COSV104428165

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant X-53201926-G-A is Benign according to our data. Variant chrX-53201926-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 94871.

BP7

Synonymous conserved (PhyloP=0.806 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00207 (233/112381) while in subpopulation NFE AF = 0.00368 (196/53269). AF 95% confidence interval is 0.00326. There are 0 homozygotes in GnomAd4. There are 56 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 56 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.1794C>T	p.Pro598Pro	synonymous	Exon 13 of 26	NP_004178.2	P41229-1
KDM5C	NM_001282622.3		c.1791C>T	p.Pro597Pro	synonymous	Exon 13 of 26	NP_001269551.1	P41229-5
KDM5C	NM_001353978.3		c.1794C>T	p.Pro598Pro	synonymous	Exon 13 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.1794C>T	p.Pro598Pro	synonymous	Exon 13 of 26	ENSP00000364550.4	P41229-1
KDM5C	ENST00000404049.7	TSL:1	c.1791C>T	p.Pro597Pro	synonymous	Exon 13 of 26	ENSP00000385394.3	P41229-5
KDM5C	ENST00000935430.1		c.1896C>T	p.Pro632Pro	synonymous	Exon 14 of 27	ENSP00000605489.1

Frequencies

GnomAD3 genomes

AF:

0.00207

AC:

233

AN:

112329

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000519

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000565

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00218

Gnomad FIN

AF:

0.00130

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00368

Gnomad OTH

AF:

0.000664

GnomAD2 exomes

AF:

0.00179

AC:

329

AN:

183514

AF XY:

0.00184

show subpopulations

Gnomad AFR exome

AF:

0.000456

Gnomad AMR exome

AF:

0.000182

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00175

Gnomad NFE exome

AF:

0.00320

Gnomad OTH exome

AF:

0.00176

GnomAD4 exome

AF:

0.00316

AC:

3475

AN:

1098148

Hom.:

Cov.:

AF XY:

0.00307

AC XY:

1115

AN XY:

363502

show subpopulations

African (AFR)

AF:

0.000455

AC:

AN:

26402

American (AMR)

AF:

0.000341

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.000103

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.000979

AC:

AN:

54147

European-Finnish (FIN)

AF:

0.00118

AC:

AN:

40532

Middle Eastern (MID)

AF:

0.00169

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.00380

AC:

3198

AN:

842038

Other (OTH)

AF:

0.00310

AC:

143

AN:

46094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

138

276

415

553

691

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

130

260

390

520

650

<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:

0.00207

AC:

233

AN:

112381

Hom.:

Cov.:

AF XY:

0.00162

AC XY:

AN XY:

34547

show subpopulations

African (AFR)

AF:

0.000518

AC:

AN:

30902

American (AMR)

AF:

0.000565

AC:

AN:

10628

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2651

East Asian (EAS)

AF:

0.00

AC:

AN:

3586

South Asian (SAS)

AF:

0.00219

AC:

AN:

2744

European-Finnish (FIN)

AF:

0.00130

AC:

AN:

6173

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.00368

AC:

196

AN:

53269

Other (OTH)

AF:

0.000656

AC:

AN:

1524

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.000829

Hom.:

Bravo

AF:

0.00179

EpiCase

AF:

0.00294

EpiControl

AF:

0.00338

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Inborn genetic diseases (1)

not specified (1)

Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

3.4

(source)

DANN

Benign

0.62

PhyloP100

0.81

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=93/7

polymorphism (auto)

(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