NM_004187.5:c.*99A>G

Variant names:

• chrX-53192868-T-C
• rs781849827
• NM_004187.5:c.*99A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_004187.5(KDM5C):​c.*99A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.059 (0 hom., 0 hem., cov: 0)
  • Exomes 𝑓: 0.030 (2 hom. 3 hem.)
  • Failed GnomAD Quality Control
• Consequence: KDM5C NM_004187.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.249
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant X-53192868-T-C is Benign according to our data. Variant chrX-53192868-T-C is described in ClinVar as Benign. ClinVar VariationId is 1296681.Status of the report is criteria_provided_single_submitter, 1 stars.

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.*99A>G		3_prime_UTR	Exon 26 of 26	NP_004178.2	P41229-1
	KDM5C	NM_001282622.3		c.*99A>G		3_prime_UTR	Exon 26 of 26	NP_001269551.1	P41229-5
	KDM5C	NM_001353978.3		c.*99A>G		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.*99A>G		3_prime_UTR	Exon 26 of 26	ENSP00000364550.4	P41229-1
	KDM5C	ENST00000404049.7	TSL:1	c.*99A>G		3_prime_UTR	Exon 26 of 26	ENSP00000385394.3	P41229-5
	KDM5C	ENST00000935430.1		c.*99A>G		3_prime_UTR	Exon 27 of 27	ENSP00000605489.1

Frequencies

GnomAD3 genomes AF: 0.0589 AC: 1302 AN: 22123 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0330

Gnomad AMI AF: 0.0484

Gnomad AMR AF: 0.0420

Gnomad ASJ AF: 0.0568

Gnomad EAS AF: 0.0484

Gnomad SAS AF: 0.0365

Gnomad FIN AF: 0.0395

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0793

Gnomad OTH AF: 0.0684

GnomAD2 exomes AF: 0.00380 AC: 195 AN: 51256 AF XY: 0.00

Gnomad AFR exome AF: 0.00351

Gnomad AMR exome AF: 0.00657

Gnomad ASJ exome AF: 0.00285

Gnomad EAS exome AF: 0.00781

Gnomad FIN exome AF: 0.000113

Gnomad NFE exome AF: 0.00421

Gnomad OTH exome AF: 0.00565

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0300 AC: 3844 AN: 128079 Hom.: 2 Cov.: 0 AF XY: 0.000116 AC XY: 3 AN XY: 25889

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

African (AFR) AF: 0.0171 AC: 70 AN: 4090

American (AMR) AF: 0.0133 AC: 64 AN: 4807

Ashkenazi Jewish (ASJ) AF: 0.0281 AC: 71 AN: 2524

East Asian (EAS) AF: 0.0150 AC: 79 AN: 5258

South Asian (SAS) AF: 0.0287 AC: 226 AN: 7875

European-Finnish (FIN) AF: 0.0169 AC: 172 AN: 10181

Middle Eastern (MID) AF: 0.0163 AC: 10 AN: 613

European-Non Finnish (NFE) AF: 0.0339 AC: 2965 AN: 87365

Other (OTH) AF: 0.0348 AC: 187 AN: 5366

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0588 AC: 1302 AN: 22155 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 3259

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

African (AFR) AF: 0.0330 AC: 219 AN: 6642

American (AMR) AF: 0.0417 AC: 86 AN: 2061

Ashkenazi Jewish (ASJ) AF: 0.0568 AC: 32 AN: 563

East Asian (EAS) AF: 0.0483 AC: 21 AN: 435

South Asian (SAS) AF: 0.0360 AC: 8 AN: 222

European-Finnish (FIN) AF: 0.0395 AC: 26 AN: 658

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 25

European-Non Finnish (NFE) AF: 0.0793 AC: 886 AN: 11175

Other (OTH) AF: 0.0673 AC: 21 AN: 312

⚠️ 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: 0.00222 Hom.: 0

ClinVar

ClinVar submissions

Significance: 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	-0.89
CADD	Benign	1.8
DANN	Benign	0.66
PhyloP100		-0.25
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: rs781849827; hg19: chrX-53222050; COSMIC: COSV104428166; COSMIC: COSV104428166;