X-53194147-T-C

Variant names:

• chrX-53194147-T-C
• rs797044473
• NM_004187.5:c.4030A>G

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.4030A>G​(p.Met1344Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: KDM5C NM_004187.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 0.618
• Publications: 1 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, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• 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=0.069123566).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM5C	NM_004187.5	MANE Select	c.4030A>G	p.Met1344Val	missense	Exon 23 of 26	NP_004178.2
	KDM5C	NM_001282622.3		c.4027A>G	p.Met1343Val	missense	Exon 23 of 26	NP_001269551.1
	KDM5C	NM_001353978.3		c.4030A>G	p.Met1344Val	missense	Exon 23 of 26	NP_001340907.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM5C	ENST00000375401.8	TSL:1 MANE Select	c.4030A>G	p.Met1344Val	missense	Exon 23 of 26	ENSP00000364550.4
	KDM5C	ENST00000404049.7	TSL:1	c.4027A>G	p.Met1343Val	missense	Exon 23 of 26	ENSP00000385394.3
	KDM5C	ENST00000375379.7	TSL:5	c.4030A>G	p.Met1344Val	missense	Exon 23 of 26	ENSP00000364528.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Sep 03, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.8
DANN	Benign	0.67
DEOGEN2	Benign	0.086	T
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	-0.14	N
PhyloP100		0.62
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.17
Sift	Benign	0.36	T
Sift4G	Benign	0.29	T
Polyphen		0.0	B
Vest4		0.24
MutPred		0.17		Gain of helix (P = 0.0696)
MVP		0.61
MPC		0.56
ClinPred		0.17	T
GERP RS		-0.97
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.086
gMVP		0.33
Mutation Taster		=99/1	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

dbSNP: rs797044473; hg19: chrX-53223329;