rs74850270

Variant names:

• chrX-53201727-C-T
• rs74850270
• NM_004187.5:c.1884G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_004187.5(KDM5C):​c.1884G>A​(p.Gln628Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00157 in 1,210,494 control chromosomes in the GnomAD database, including 30 homozygotes. There are 508 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (11 hom., 238 hem., cov: 23)
  • Exomes 𝑓: 0.00091 (19 hom. 270 hem.)
• Consequence: KDM5C NM_004187.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.77
• 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, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• X-linked syndromic intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant X-53201727-C-T is Benign according to our data. Variant chrX-53201727-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.77 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00802 (901/112368) while in subpopulation AFR AF = 0.0277 (857/30933). AF 95% confidence interval is 0.0262. There are 11 homozygotes in GnomAd4. There are 238 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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.1884G>A	p.Gln628Gln	synonymous	Exon 14 of 26	NP_004178.2
	KDM5C	NM_001282622.3		c.1881G>A	p.Gln627Gln	synonymous	Exon 14 of 26	NP_001269551.1
	KDM5C	NM_001353978.3		c.1884G>A	p.Gln628Gln	synonymous	Exon 14 of 26	NP_001340907.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM5C	ENST00000375401.8	TSL:1 MANE Select	c.1884G>A	p.Gln628Gln	synonymous	Exon 14 of 26	ENSP00000364550.4
	KDM5C	ENST00000404049.7	TSL:1	c.1881G>A	p.Gln627Gln	synonymous	Exon 14 of 26	ENSP00000385394.3
	KDM5C	ENST00000935430.1		c.1986G>A	p.Gln662Gln	synonymous	Exon 15 of 27	ENSP00000605489.1

Frequencies

GnomAD3 genomes AF: 0.00794 AC: 892 AN: 112314 Hom.: 11 Cov.: 23

Gnomad AFR AF: 0.0274

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00254

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000364

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00661

GnomAD2 exomes AF: 0.00254 AC: 464 AN: 182732 AF XY: 0.00171

Gnomad AFR exome AF: 0.0318

Gnomad AMR exome AF: 0.00117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00111

GnomAD4 exome AF: 0.000908 AC: 997 AN: 1098126 Hom.: 19 Cov.: 31 AF XY: 0.000743 AC XY: 270 AN XY: 363488

African (AFR) AF: 0.0301 AC: 796 AN: 26403

American (AMR) AF: 0.00125 AC: 44 AN: 35196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.0000554 AC: 3 AN: 54124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40519

Middle Eastern (MID) AF: 0.00145 AC: 6 AN: 4137

European-Non Finnish (NFE) AF: 0.0000511 AC: 43 AN: 842064

Other (OTH) AF: 0.00228 AC: 105 AN: 46095

GnomAD4 genome AF: 0.00802 AC: 901 AN: 112368 Hom.: 11 Cov.: 23 AF XY: 0.00689 AC XY: 238 AN XY: 34522

African (AFR) AF: 0.0277 AC: 857 AN: 30933

American (AMR) AF: 0.00244 AC: 26 AN: 10652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2658

East Asian (EAS) AF: 0.00 AC: 0 AN: 3571

South Asian (SAS) AF: 0.000366 AC: 1 AN: 2735

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.000132 AC: 7 AN: 53203

Other (OTH) AF: 0.00652 AC: 10 AN: 1534

Alfa AF: 0.00486 Hom.: 25

Bravo AF: 0.00917

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	7.4
DANN	Benign	0.62
PhyloP100		1.8
Mutation Taster		=100/0	polymorphism (auto)

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: rs74850270; hg19: chrX-53230909; COSMIC: COSV104428175;