X-53192881-C-A

Variant names:

• chrX-53192881-C-A
• rs372057894
• NM_004187.5:c.*86G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004187.5(KDM5C):​c.*86G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000209 in 957,668 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 17)
  • Exomes 𝑓: 0.0000021 (0 hom. 0 hem.)
• Consequence: KDM5C NM_004187.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.79
• Publications: 0 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• X-linked syndromic intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).

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.*86G>T		3_prime_UTR	Exon 26 of 26	NP_004178.2	P41229-1
	KDM5C	NM_001282622.3		c.*86G>T		3_prime_UTR	Exon 26 of 26	NP_001269551.1	P41229-5
	KDM5C	NM_001353978.3		c.*86G>T		3_prime_UTR	Exon 26 of 26	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.*86G>T		3_prime_UTR	Exon 26 of 26	ENSP00000364550.4	P41229-1
	KDM5C	ENST00000404049.7	TSL:1	c.*86G>T		3_prime_UTR	Exon 26 of 26	ENSP00000385394.3	P41229-5
	KDM5C	ENST00000935430.1		c.*86G>T		3_prime_UTR	Exon 27 of 27	ENSP00000605489.1

Frequencies

GnomAD3 genomes Cov.: 17

GnomAD2 exomes AF: 0.0000105 AC: 1 AN: 95547 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000790

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: 0.00

GnomAD4 exome AF: 0.00000209 AC: 2 AN: 957668 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 264082

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000448 AC: 1 AN: 22308

American (AMR) AF: 0.0000496 AC: 1 AN: 20150

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14892

East Asian (EAS) AF: 0.00 AC: 0 AN: 27886

South Asian (SAS) AF: 0.00 AC: 0 AN: 37784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35559

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3187

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 755751

Other (OTH) AF: 0.00 AC: 0 AN: 40151

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 17

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	12
DANN	Benign	0.85
PhyloP100		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Other links and lift over

dbSNP: rs372057894; hg19: chrX-53222063;