rs45442400

Positions:

• chrX-53194736-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_004187.5(KDM5C):​c.3441C>T​(p.Ile1147=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,207,651 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 42 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.00012 (0 hom. 40 hem.)
• Consequence: KDM5C NM_004187.5 splice_region, synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.211

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant X-53194736-G-A is Benign according to our data. Variant chrX-53194736-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 599443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.211 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KDM5C	NM_004187.5	c.3441C>T	p.Ile1147=	splice_region_variant, synonymous_variant	23/26	ENST00000375401.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KDM5C	ENST00000375401.8	c.3441C>T	p.Ile1147=	splice_region_variant, synonymous_variant	23/26	1	NM_004187.5	P5

Frequencies

GnomAD3 genomes AF: 0.0000363 AC: 4 AN: 110081 Hom.: 0 Cov.: 23 AF XY: 0.0000618 AC XY: 2 AN XY: 32373

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000761

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000388 AC: 7 AN: 180223 Hom.: 0 AF XY: 0.0000455 AC XY: 3 AN XY: 65875

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000366

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000629

Gnomad OTH exome AF: 0.000223

GnomAD4 exome AF: 0.000125 AC: 137 AN: 1097570 Hom.: 0 Cov.: 32 AF XY: 0.000110 AC XY: 40 AN XY: 363008

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.000114

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000156

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome AF: 0.0000363 AC: 4 AN: 110081 Hom.: 0 Cov.: 23 AF XY: 0.0000618 AC XY: 2 AN XY: 32373

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000761

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000604

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Dec 07, 2017

BS2, BP5; This alteration was seen in a healthy adult where full penetrance of the disorder is expected at an early age, and was found in a case with an alternate molecular basis for disease. -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 06, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	6.7
DANN	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs45442400; hg19: chrX-53223918; COSMIC: COSV100949280; COSMIC: COSV100949280;