NM_004187.5:c.*43G>A

Variant names:

• chrX-53192924-C-T
• rs781971436
• NM_004187.5:c.*43G>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.*43G>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 0.0000263 in 950,652 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. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000011 (0 hom., 0 hem., cov: 16)
  • Exomes 𝑓: 0.000028 (0 hom. 4 hem.)
• Consequence: KDM5C NM_004187.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.39
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant X-53192924-C-T is Benign according to our data. Variant chrX-53192924-C-T is described in ClinVar as [Benign]. Clinvar id is 1258823.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000278 (24/863647) while in subpopulation AMR AF = 0.00116 (21/18136). AF 95% confidence interval is 0.000776. There are 0 homozygotes in GnomAdExome4. There are 4 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDM5C	NM_004187.5	c.*43G>A		3_prime_UTR_variant	Exon 26 of 26	ENST00000375401.8	NP_004178.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDM5C	ENST00000375401.8	c.*43G>A		3_prime_UTR_variant	Exon 26 of 26	1	NM_004187.5	ENSP00000364550.4

Frequencies

GnomAD3 genomes AF: 0.0000115 AC: 1 AN: 87005 Hom.: 0 Cov.: 16

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000150

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

GnomAD2 exomes AF: 0.000158 AC: 20 AN: 126670 AF XY: 0.0000977

Gnomad AFR exome AF: 0.00

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: 0.00

Gnomad OTH exome AF: 0.000351

GnomAD4 exome AF: 0.0000278 AC: 24 AN: 863647 Hom.: 0 Cov.: 30 AF XY: 0.0000148 AC XY: 4 AN XY: 270279

African (AFR) AF: 0.00 AC: 0 AN: 19537

American (AMR) AF: 0.00116 AC: 21 AN: 18136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9221

East Asian (EAS) AF: 0.00 AC: 0 AN: 14855

South Asian (SAS) AF: 0.0000238 AC: 1 AN: 42037

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2889

European-Non Finnish (NFE) AF: 0.00000143 AC: 1 AN: 700697

Other (OTH) AF: 0.0000314 AC: 1 AN: 31887

GnomAD4 genome AF: 0.0000115 AC: 1 AN: 87005 Hom.: 0 Cov.: 16 AF XY: 0.00 AC XY: 0 AN XY: 18427

African (AFR) AF: 0.00 AC: 0 AN: 24176

American (AMR) AF: 0.000150 AC: 1 AN: 6687

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2351

East Asian (EAS) AF: 0.00 AC: 0 AN: 2208

South Asian (SAS) AF: 0.00 AC: 0 AN: 1184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2996

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 155

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 45542

Other (OTH) AF: 0.00 AC: 0 AN: 1166

Alfa AF: 0.0000980 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Apr 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	15
DANN	Benign	0.90
PhyloP100		1.4
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: rs781971436; hg19: chrX-53222106;