rs398124111

Variant names:

• chrX-53197882-A-AAGT
• rs398124111
• NM_004187.5:c.2517-9_2517-7dupACT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_004187.5(KDM5C):​c.2517-9_2517-7dupACT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.014 in 1,161,391 control chromosomes in the GnomAD database, including 83 homozygotes. There are 5,002 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (2 hom., 232 hem., cov: 22)
  • Exomes 𝑓: 0.014 (81 hom. 4770 hem.)
• Consequence: KDM5C NM_004187.5 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.48
• Publications: 2 publications found

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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant X-53197882-A-AAGT is Benign according to our data. Variant chrX-53197882-A-AAGT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00905 (1011/111747) while in subpopulation NFE AF = 0.0152 (807/53084). AF 95% confidence interval is 0.0143. There are 2 homozygotes in GnomAd4. There are 232 alleles in the male GnomAd4 subpopulation. Median coverage is 22. 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM5C	NM_004187.5	MANE Select	c.2517-9_2517-7dupACT		splice_region intron	N/A	NP_004178.2	P41229-1
	KDM5C	NM_001282622.3		c.2514-9_2514-7dupACT		splice_region intron	N/A	NP_001269551.1	P41229-5
	KDM5C	NM_001353978.3		c.2517-9_2517-7dupACT		splice_region intron	N/A	NP_001340907.1	P41229-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM5C	ENST00000375401.8	TSL:1 MANE Select	c.2517-7_2517-6insACT		splice_region intron	N/A	ENSP00000364550.4	P41229-1
	KDM5C	ENST00000404049.7	TSL:1	c.2514-7_2514-6insACT		splice_region intron	N/A	ENSP00000385394.3	P41229-5
	KDM5C	ENST00000935430.1		c.2619-7_2619-6insACT		splice_region intron	N/A	ENSP00000605489.1

Frequencies

GnomAD3 genomes AF: 0.00905 AC: 1011 AN: 111695 Hom.: 2 Cov.: 22

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.00735

Gnomad AMR AF: 0.00493

Gnomad ASJ AF: 0.0106

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00148

Gnomad FIN AF: 0.00725

Gnomad MID AF: 0.00837

Gnomad NFE AF: 0.0152

Gnomad OTH AF: 0.00801

GnomAD2 exomes AF: 0.00994 AC: 1325 AN: 133366 AF XY: 0.00963

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00792

Gnomad ASJ exome AF: 0.0157

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00873

Gnomad NFE exome AF: 0.0148

Gnomad OTH exome AF: 0.0165

GnomAD4 exome AF: 0.0145 AC: 15211 AN: 1049644 Hom.: 81 Cov.: 26 AF XY: 0.0145 AC XY: 4770 AN XY: 328228

African (AFR) AF: 0.00202 AC: 51 AN: 25274

American (AMR) AF: 0.00765 AC: 237 AN: 30967

Ashkenazi Jewish (ASJ) AF: 0.0137 AC: 255 AN: 18666

East Asian (EAS) AF: 0.00 AC: 0 AN: 28395

South Asian (SAS) AF: 0.00438 AC: 220 AN: 50232

European-Finnish (FIN) AF: 0.00891 AC: 344 AN: 38588

Middle Eastern (MID) AF: 0.00617 AC: 25 AN: 4052

European-Non Finnish (NFE) AF: 0.0167 AC: 13547 AN: 809104

Other (OTH) AF: 0.0120 AC: 532 AN: 44366

GnomAD4 genome AF: 0.00905 AC: 1011 AN: 111747 Hom.: 2 Cov.: 22 AF XY: 0.00684 AC XY: 232 AN XY: 33927

African (AFR) AF: 0.00185 AC: 57 AN: 30739

American (AMR) AF: 0.00493 AC: 52 AN: 10555

Ashkenazi Jewish (ASJ) AF: 0.0106 AC: 28 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3542

South Asian (SAS) AF: 0.00149 AC: 4 AN: 2689

European-Finnish (FIN) AF: 0.00725 AC: 44 AN: 6072

Middle Eastern (MID) AF: 0.00917 AC: 2 AN: 218

European-Non Finnish (NFE) AF: 0.0152 AC: 807 AN: 53084

Other (OTH) AF: 0.00791 AC: 12 AN: 1518

Alfa AF: 0.0107 Hom.: 78

Bravo AF: 0.00895

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	KDM5C-related disorder (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs398124111; hg19: chrX-53227064; COSMIC: COSV104428139;