rs1245355138

Variant names:

• chrX-53193084-G-T
• rs1245355138
• NM_004187.5:c.4566C>A

Your query was ambiguous. Multiple possible variants found:

• chrX-53193084-G-T
• chrX-53193084-G-A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004187.5(KDM5C):​c.4566C>A​(p.Asn1522Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000058 in 1,207,054 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1522D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000091 (0 hom., 0 hem., cov: 21)
  • Exomes 𝑓: 0.0000055 (0 hom. 4 hem.)
• Consequence: KDM5C NM_004187.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 1.50
• 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, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• X-linked syndromic intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19687027).
• BS2: High Hemizygotes in GnomAdExome4 at 4 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.4566C>A	p.Asn1522Lys	missense	Exon 26 of 26	NP_004178.2	P41229-1
	KDM5C	NM_001282622.3		c.4563C>A	p.Asn1521Lys	missense	Exon 26 of 26	NP_001269551.1	P41229-5
	KDM5C	NM_001353978.3		c.4557C>A	p.Asn1519Lys	missense	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.4566C>A	p.Asn1522Lys	missense	Exon 26 of 26	ENSP00000364550.4	P41229-1
	KDM5C	ENST00000404049.7	TSL:1	c.4563C>A	p.Asn1521Lys	missense	Exon 26 of 26	ENSP00000385394.3	P41229-5
	KDM5C	ENST00000935430.1		c.4668C>A	p.Asn1556Lys	missense	Exon 27 of 27	ENSP00000605489.1

Frequencies

GnomAD3 genomes AF: 0.00000908 AC: 1 AN: 110088 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.0000331

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 6 AN: 1096966 Hom.: 0 Cov.: 33 AF XY: 0.0000110 AC XY: 4 AN XY: 362444

African (AFR) AF: 0.000114 AC: 3 AN: 26385

American (AMR) AF: 0.00 AC: 0 AN: 35111

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19337

East Asian (EAS) AF: 0.00 AC: 0 AN: 30190

South Asian (SAS) AF: 0.00 AC: 0 AN: 53938

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40463

Middle Eastern (MID) AF: 0.000244 AC: 1 AN: 4104

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841415

Other (OTH) AF: 0.0000435 AC: 2 AN: 46023

GnomAD4 genome AF: 0.00000908 AC: 1 AN: 110088 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 32364

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

African (AFR) AF: 0.0000331 AC: 1 AN: 30170

American (AMR) AF: 0.00 AC: 0 AN: 10514

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2621

East Asian (EAS) AF: 0.00 AC: 0 AN: 3388

South Asian (SAS) AF: 0.00 AC: 0 AN: 2570

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5934

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 235

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52514

Other (OTH) AF: 0.00 AC: 0 AN: 1481

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	not specified (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	0.15
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.5
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.18
Sift	Uncertain	0.024	D
Sift4G	Benign	0.28	T
Polyphen		0.0080	B
Vest4		0.092
MutPred		0.15		Gain of ubiquitination at N1522 (P = 0)
MVP		0.66
MPC		0.64
ClinPred		0.63	D
GERP RS		3.7
Varity_R		0.21
gMVP		0.29
Mutation Taster		=97/3	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: rs1245355138; hg19: chrX-53222266;