X-53192835-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_001146702.2(KDM5C):c.4049C>G(p.Pro1350Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000605 in 1,091,199 control chromosomes in the GnomAD database, including 1 homozygotes. There are 12 hemizygotes 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. Variant has been reported in ClinVar as not provided (no stars). Synonymous variant affecting the same amino acid position (i.e. P1350P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., 8 hem., cov: 19)

Exomes 𝑓: 0.000029 ( 1 hom. 4 hem. )

Consequence

KDM5C
NM_001146702.2 missense, splice_region

Scores

Splicing: ADA: 0.00006871

Clinical Significance

not provided no classification provided O:1

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1330562).

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000375 (37/98685) while in subpopulation AMR AF = 0.00379 (34/8977). AF 95% confidence interval is 0.00279. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 19. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Hemizygotes in GnomAd4 at 8 XL gene

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>G		3_prime_UTR	Exon 26 of 26	NP_004178.2
KDM5C	NM_001146702.2		c.4049C>G	p.Pro1350Arg	missense splice_region	Exon 24 of 24	NP_001140174.1
KDM5C	NM_001282622.3		c.*132C>G		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>G		3_prime_UTR	Exon 26 of 26	ENSP00000364550.4
KDM5C	ENST00000404049.7	TSL:1	c.*132C>G		3_prime_UTR	Exon 26 of 26	ENSP00000385394.3
KDM5C	ENST00000452825.7	TSL:5	c.4049C>G	p.Pro1350Arg	missense splice_region	Exon 24 of 24	ENSP00000445176.1

Frequencies

GnomAD3 genomes

AF:

0.000375

AC:

AN:

98628

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00379

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:

0.00224

GnomAD2 exomes

AF:

0.0000493

AC:

AN:

101407

AF XY:

0.0000777

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000179

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:

0.000722

GnomAD4 exome

AF:

0.0000292

AC:

AN:

992514

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

297710

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23843

American (AMR)

AF:

0.000681

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:

771080

Other (OTH)

AF:

0.000264

AC:

AN:

41676

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.582

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:

0.000375

AC:

AN:

98685

Hom.:

Cov.:

AF XY:

0.000352

AC XY:

AN XY:

22703

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27737

American (AMR)

AF:

0.00379

AC:

AN:

8977

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2461

East Asian (EAS)

AF:

0.00

AC:

AN:

2886

South Asian (SAS)

AF:

0.00

AC:

AN:

1884

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4317

Middle Eastern (MID)

AF:

0.00

AC:

AN:

179

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

48296

Other (OTH)

AF:

0.00220

AC:

AN:

1361

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

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:

0.00

Hom.:

Bravo

AF:

0.000986

ExAC

AF:

0.0000297

AC:

ClinVar

ClinVar submissions as Germline

Significance:not provided

Revision:no classification provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.40

CADD

Benign

7.0

(source)

DANN

Benign

0.87

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.24

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.82

PhyloP100

0.89

PROVEAN

Benign

0.25

REVEL

Benign

0.10

Sift

Benign

0.27

Sift4G

Benign

0.16

Vest4

0.48

MutPred

0.51

Loss of loop (P = 0.0073)

MVP

0.63

ClinPred

0.026

GERP RS

0.98

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000069

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over