dbSNP rs76525703: KDM5C:p.Thr1180Thr (chrX-53194637-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_004187.5(KDM5C):c.3540G>A(p.Thr1180Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000576 in 1,210,404 control chromosomes in the GnomAD database, including 3 homozygotes. There are 194 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0027 ( 2 hom., 90 hem., cov: 23)

Exomes 𝑓: 0.00035 ( 1 hom. 104 hem. )

Consequence

KDM5C
NM_004187.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.264

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

KDM5C links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_004187.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant X-53194637-C-T is Benign according to our data. Variant chrX-53194637-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 283211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.264 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00274 (308/112303) while in subpopulation AFR AF = 0.00947 (293/30944). AF 95% confidence interval is 0.00858. There are 2 homozygotes in GnomAd4. There are 90 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 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.3540G>A	p.Thr1180Thr	synonymous	Exon 23 of 26	NP_004178.2	P41229-1
KDM5C	NM_001282622.3		c.3537G>A	p.Thr1179Thr	synonymous	Exon 23 of 26	NP_001269551.1	P41229-5
KDM5C	NM_001353978.3		c.3540G>A	p.Thr1180Thr	synonymous	Exon 23 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.3540G>A	p.Thr1180Thr	synonymous	Exon 23 of 26	ENSP00000364550.4	P41229-1
KDM5C	ENST00000404049.7	TSL:1	c.3537G>A	p.Thr1179Thr	synonymous	Exon 23 of 26	ENSP00000385394.3	P41229-5
KDM5C	ENST00000935430.1		c.3642G>A	p.Thr1214Thr	synonymous	Exon 24 of 27	ENSP00000605489.1

Frequencies

GnomAD3 genomes

AF:

0.00273

AC:

307

AN:

112249

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00942

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000282

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000564

Gnomad OTH

AF:

0.00329

GnomAD2 exomes

AF:

0.000891

AC:

162

AN:

181782

AF XY:

0.000628

show subpopulations

Gnomad AFR exome

AF:

0.0108

Gnomad AMR exome

AF:

0.000511

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000744

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000354

AC:

389

AN:

1098101

Hom.:

Cov.:

AF XY:

0.000286

AC XY:

104

AN XY:

363457

show subpopulations

African (AFR)

AF:

0.0100

AC:

265

AN:

26402

American (AMR)

AF:

0.000483

AC:

AN:

35196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19383

East Asian (EAS)

AF:

0.00

AC:

AN:

30201

South Asian (SAS)

AF:

0.0000554

AC:

AN:

54110

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40525

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.0000891

AC:

AN:

842051

Other (OTH)

AF:

0.000629

AC:

AN:

46096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

103

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:

0.00274

AC:

308

AN:

112303

Hom.:

Cov.:

AF XY:

0.00261

AC XY:

AN XY:

34477

show subpopulations

African (AFR)

AF:

0.00947

AC:

293

AN:

30944

American (AMR)

AF:

0.000560

AC:

AN:

10720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2659

East Asian (EAS)

AF:

0.000283

AC:

AN:

3529

South Asian (SAS)

AF:

0.00

AC:

AN:

2694

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6161

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.0000564

AC:

AN:

53152

Other (OTH)

AF:

0.00325

AC:

AN:

1539

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

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:

0.00125

Hom.:

Bravo

AF:

0.00335

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

KDM5C-related disorder (1)

not provided (1)

not specified (1)

Spastic paraplegia (1)

Syndromic X-linked intellectual disability Claes-Jensen type (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.063

(source)

DANN

Benign

0.54

PhyloP100

-0.26

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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