X-53192985-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_004187.5(KDM5C):c.4665G>A(p.Pro1555=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000481 in 1,164,861 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 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 0.000048 (0 hom., 1 hem., cov: 20)
  • Exomes 𝑓: 0.000048 (0 hom. 15 hem.)
• Consequence: KDM5C NM_004187.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.87

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant X-53192985-C-T is Benign according to our data. Variant chrX-53192985-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1579968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.87 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KDM5C	NM_004187.5	c.4665G>A	p.Pro1555=	synonymous_variant	26/26	ENST00000375401.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KDM5C	ENST00000375401.8	c.4665G>A	p.Pro1555=	synonymous_variant	26/26	1	NM_004187.5	P5

Frequencies

GnomAD3 genomes AF: 0.0000477 AC: 5 AN: 104849 Hom.: 0 Cov.: 20 AF XY: 0.0000352 AC XY: 1 AN XY: 28425

Gnomad AFR AF: 0.0000349

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000388

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000390

Gnomad OTH AF: 0.000708

GnomAD3 exomes AF: 0.0000201 AC: 3 AN: 149261 Hom.: 0 AF XY: 0.0000210 AC XY: 1 AN XY: 47589

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000433

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000849

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000147

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000481 AC: 51 AN: 1060012 Hom.: 0 Cov.: 33 AF XY: 0.0000440 AC XY: 15 AN XY: 340910

Gnomad4 AFR exome AF: 0.0000393

Gnomad4 AMR exome AF: 0.0000319

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000622

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000536

Gnomad4 OTH exome AF: 0.0000451

GnomAD4 genome AF: 0.0000477 AC: 5 AN: 104849 Hom.: 0 Cov.: 20 AF XY: 0.0000352 AC XY: 1 AN XY: 28425

Gnomad4 AFR AF: 0.0000349

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000388

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000390

Gnomad4 OTH AF: 0.000708

Bravo AF: 0.0000264

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 04, 2023

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 30, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
Cadd	Benign	1.0
Dann	Benign	0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs370930723; hg19: chrX-53222167; COSMIC: COSV64766002; COSMIC: COSV64766002;