X-53192843-C-G

Variant names:

• chrX-53192843-C-G
• rs781897787
• NM_004187.5:c.*124G>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001146702.2(KDM5C):​c.4047-6G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000068 (0 hom., 0 hem., cov: 18)
  • Exomes 𝑓: 0.018 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: KDM5C NM_001146702.2 splice_region, intron
• Scores: Splicing: ADA: 0.000009886
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.911
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant X-53192843-C-G is Benign according to our data. Variant chrX-53192843-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2283519.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001146702.2. 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.*124G>C		3_prime_UTR	Exon 26 of 26	NP_004178.2	P41229-1
	KDM5C	NM_001282622.3		c.*124G>C		3_prime_UTR	Exon 26 of 26	NP_001269551.1	P41229-5
	KDM5C	NM_001353978.3		c.*124G>C		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.*124G>C		3_prime_UTR	Exon 26 of 26	ENSP00000364550.4	P41229-1
	KDM5C	ENST00000404049.7	TSL:1	c.*124G>C		3_prime_UTR	Exon 26 of 26	ENSP00000385394.3	P41229-5
	KDM5C	ENST00000935430.1		c.*124G>C		3_prime_UTR	Exon 27 of 27	ENSP00000605489.1

Frequencies

GnomAD3 genomes AF: 0.0000677 AC: 6 AN: 88594 Hom.: 0 Cov.: 18

Gnomad AFR AF: 0.0000393

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000434

Gnomad EAS AF: 0.000484

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000443

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0177 AC: 8192 AN: 463493 Hom.: 0 Cov.: 12 AF XY: 0.00 AC XY: 0 AN XY: 120975

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

African (AFR) AF: 0.0176 AC: 218 AN: 12381

American (AMR) AF: 0.00288 AC: 59 AN: 20474

Ashkenazi Jewish (ASJ) AF: 0.00859 AC: 89 AN: 10355

East Asian (EAS) AF: 0.0137 AC: 206 AN: 15059

South Asian (SAS) AF: 0.00391 AC: 137 AN: 35074

European-Finnish (FIN) AF: 0.00249 AC: 62 AN: 24859

Middle Eastern (MID) AF: 0.00692 AC: 12 AN: 1734

European-Non Finnish (NFE) AF: 0.0219 AC: 7075 AN: 323282

Other (OTH) AF: 0.0165 AC: 334 AN: 20275

⚠️ 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: 0.0000677 AC: 6 AN: 88669 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 18593

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

African (AFR) AF: 0.0000393 AC: 1 AN: 25469

American (AMR) AF: 0.000130 AC: 1 AN: 7666

Ashkenazi Jewish (ASJ) AF: 0.000434 AC: 1 AN: 2302

East Asian (EAS) AF: 0.000485 AC: 1 AN: 2063

South Asian (SAS) AF: 0.00 AC: 0 AN: 1242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2882

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 133

European-Non Finnish (NFE) AF: 0.0000443 AC: 2 AN: 45163

Other (OTH) AF: 0.00 AC: 0 AN: 1230

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000554447), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	-	1	KDM5C-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.5
DANN	Benign	0.64
PhyloP100		0.91
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000099
dbscSNV1_RF	Benign	0.0
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: rs781897787; hg19: chrX-53222025;