NM_004187.5:c.3442G>A

Variant names:

• chrX-53194735-C-T
• rs782205045
• NM_004187.5:c.3442G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_004187.5(KDM5C):​c.3442G>A​(p.Val1148Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000128 in 1,097,585 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000013 (0 hom. 5 hem.)
• Consequence: KDM5C NM_004187.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.80
• 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: 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13291487).
• BP6: Variant X-53194735-C-T is Benign according to our data. Variant chrX-53194735-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 522629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 5 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.3442G>A	p.Val1148Met	missense	Exon 23 of 26	NP_004178.2	P41229-1
	KDM5C	NM_001282622.3		c.3439G>A	p.Val1147Met	missense	Exon 23 of 26	NP_001269551.1	P41229-5
	KDM5C	NM_001353978.3		c.3442G>A	p.Val1148Met	missense	Exon 23 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.3442G>A	p.Val1148Met	missense	Exon 23 of 26	ENSP00000364550.4	P41229-1
	KDM5C	ENST00000404049.7	TSL:1	c.3439G>A	p.Val1147Met	missense	Exon 23 of 26	ENSP00000385394.3	P41229-5
	KDM5C	ENST00000935430.1		c.3544G>A	p.Val1182Met	missense	Exon 24 of 27	ENSP00000605489.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000111 AC: 2 AN: 180221 AF XY: 0.0000152

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000126

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000128 AC: 14 AN: 1097585 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 5 AN XY: 363009

African (AFR) AF: 0.00 AC: 0 AN: 26376

American (AMR) AF: 0.00 AC: 0 AN: 35171

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19374

East Asian (EAS) AF: 0.0000662 AC: 2 AN: 30198

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54028

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3984

European-Non Finnish (NFE) AF: 0.00000950 AC: 8 AN: 841926

Other (OTH) AF: 0.0000651 AC: 3 AN: 46050

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Spastic paraplegia (1)
-	-	1	Syndromic X-linked intellectual disability Claes-Jensen type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	-0.030	N
PhyloP100		1.8
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.20
Sift	Benign	0.14	T
Sift4G	Benign	0.16	T
Polyphen		0.15	B
Vest4		0.26
MutPred		0.38		Gain of disorder (P = 0.0471)
MVP		0.70
MPC		0.56
ClinPred		0.31	T
GERP RS		3.9
Varity_R		0.14
gMVP		0.82
Mutation Taster		=92/8	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs782205045; hg19: chrX-53223917; COSMIC: COSV64765058;