NM_004187.5:c.*149T>C

Variant names:

• chrX-53192818-A-G
• NM_004187.5:c.*149T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004187.5(KDM5C):​c.*149T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000193 in 1,037,476 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 19)
  • Exomes 𝑓: 0.0000019 (0 hom. 0 hem.)
• Consequence: KDM5C NM_004187.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.43
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20832425).

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.*149T>C		3_prime_UTR	Exon 26 of 26	NP_004178.2	P41229-1
	KDM5C	NM_001146702.2		c.4066T>C	p.Cys1356Arg	missense	Exon 24 of 24	NP_001140174.1	A0A6M4C8G8
	KDM5C	NM_001282622.3		c.*149T>C		3_prime_UTR	Exon 26 of 26	NP_001269551.1	P41229-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM5C	ENST00000375401.8	TSL:1 MANE Select	c.*149T>C		3_prime_UTR	Exon 26 of 26	ENSP00000364550.4	P41229-1
	KDM5C	ENST00000404049.7	TSL:1	c.*149T>C		3_prime_UTR	Exon 26 of 26	ENSP00000385394.3	P41229-5
	KDM5C	ENST00000452825.7	TSL:5	c.4066T>C	p.Cys1356Arg	missense	Exon 24 of 24	ENSP00000445176.1	P41229-4

Frequencies

GnomAD3 genomes Cov.: 19

GnomAD4 exome AF: 0.00000193 AC: 2 AN: 1037476 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 329004

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

African (AFR) AF: 0.00 AC: 0 AN: 24611

American (AMR) AF: 0.00 AC: 0 AN: 27683

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18341

East Asian (EAS) AF: 0.00 AC: 0 AN: 26865

South Asian (SAS) AF: 0.00 AC: 0 AN: 48545

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37371

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3222

European-Non Finnish (NFE) AF: 0.00000248 AC: 2 AN: 807260

Other (OTH) AF: 0.00 AC: 0 AN: 43578

⚠️ 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.: 19

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	13
DANN	Benign	0.92
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.20	T
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.71	T
PhyloP100		2.4
PROVEAN	Benign	1.6	N
REVEL	Benign	0.19
Sift	Benign	0.21	T
Sift4G	Uncertain	0.060	T
Vest4		0.19
MutPred		0.49		Gain of disorder (P = 0.0377)
MVP		0.62
ClinPred		0.29	T
GERP RS		2.6
Mutation Taster		=91/9	polymorphism

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

hg19: chrX-53222000;