chrX-53192881-C-T

Variant names:

• chrX-53192881-C-T
• rs372057894
• NM_004187.5:c.*86G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004187.5(KDM5C):​c.*86G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000588 in 1,052,812 control chromosomes in the GnomAD database, including 5 homozygotes. There are 107 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 0.0033 (4 hom., 37 hem., cov: 17)
  • Exomes 𝑓: 0.00032 (1 hom. 70 hem.)
• Consequence: KDM5C NM_004187.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.79
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant X-53192881-C-T is Benign according to our data. Variant chrX-53192881-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1217458.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00332 (316/95136) while in subpopulation AFR AF = 0.0117 (307/26143). AF 95% confidence interval is 0.0107. There are 4 homozygotes in GnomAd4. There are 37 alleles in the male GnomAd4 subpopulation. Median coverage is 17. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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.*86G>A		3_prime_UTR	Exon 26 of 26	NP_004178.2	P41229-1
	KDM5C	NM_001282622.3		c.*86G>A		3_prime_UTR	Exon 26 of 26	NP_001269551.1	P41229-5
	KDM5C	NM_001353978.3		c.*86G>A		3_prime_UTR	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.*86G>A		3_prime_UTR	Exon 26 of 26	ENSP00000364550.4	P41229-1
	KDM5C	ENST00000404049.7	TSL:1	c.*86G>A		3_prime_UTR	Exon 26 of 26	ENSP00000385394.3	P41229-5
	KDM5C	ENST00000935430.1		c.*86G>A		3_prime_UTR	Exon 27 of 27	ENSP00000605489.1

Frequencies

GnomAD3 genomes AF: 0.00331 AC: 315 AN: 95098 Hom.: 4 Cov.: 17

Gnomad AFR AF: 0.0117

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000553

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: 0.0000429

Gnomad OTH AF: 0.00161

GnomAD2 exomes AF: 0.00141 AC: 135 AN: 95547 AF XY: 0.000992

Gnomad AFR exome AF: 0.0161

Gnomad AMR exome AF: 0.000632

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000445

GnomAD4 exome AF: 0.000316 AC: 303 AN: 957676 Hom.: 1 Cov.: 22 AF XY: 0.000265 AC XY: 70 AN XY: 264086

African (AFR) AF: 0.0114 AC: 254 AN: 22307

American (AMR) AF: 0.000447 AC: 9 AN: 20150

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14892

East Asian (EAS) AF: 0.00 AC: 0 AN: 27888

South Asian (SAS) AF: 0.0000529 AC: 2 AN: 37786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35560

Middle Eastern (MID) AF: 0.000628 AC: 2 AN: 3187

European-Non Finnish (NFE) AF: 0.00000265 AC: 2 AN: 755753

Other (OTH) AF: 0.000847 AC: 34 AN: 40153

GnomAD4 genome AF: 0.00332 AC: 316 AN: 95136 Hom.: 4 Cov.: 17 AF XY: 0.00182 AC XY: 37 AN XY: 20360

African (AFR) AF: 0.0117 AC: 307 AN: 26143

American (AMR) AF: 0.000552 AC: 5 AN: 9050

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2383

East Asian (EAS) AF: 0.00 AC: 0 AN: 2757

South Asian (SAS) AF: 0.00 AC: 0 AN: 1694

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4492

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 170

European-Non Finnish (NFE) AF: 0.0000429 AC: 2 AN: 46626

Other (OTH) AF: 0.00158 AC: 2 AN: 1263

Alfa AF: 0.00209 Hom.: 7

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	12
DANN	Benign	0.85
PhyloP100		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs372057894; hg19: chrX-53222063;