X-53192975-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BP4_Moderate BP6_Moderate

The NM_004187.5(KDM5C):c.4675C>A(p.Gln1559Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000333 in 1,051,433 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1559E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.000033 (0 hom. 12 hem.)
• Consequence: KDM5C NM_004187.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.28

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 Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KDM5C
• BP4: Computational evidence support a benign effect (MetaRNN=0.1894806).
• BP6: Variant X-53192975-G-T is Benign according to our data. Variant chrX-53192975-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 1211975.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KDM5C	NM_004187.5	c.4675C>A	p.Gln1559Lys	missense_variant	26/26	ENST00000375401.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KDM5C	ENST00000375401.8	c.4675C>A	p.Gln1559Lys	missense_variant	26/26	1	NM_004187.5	P5

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome AF: 0.0000333 AC: 35 AN: 1051433 Hom.: 0 Cov.: 33 AF XY: 0.0000357 AC XY: 12 AN XY: 335999

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000392

Gnomad4 OTH exome AF: 0.0000685

GnomAD4 genome Cov.: 20

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 05, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.0083	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	20
Dann	Benign	0.93
DEOGEN2	Benign	0.092	T;.;.;.
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	0.46	N;.;.;.
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.18	N;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.28	T;T;T;T
Sift4G	Uncertain	0.054	T;T;T;T
Polyphen		0.049	B;.;.;.
Vest4		0.29
MVP		0.85
MPC		0.70
ClinPred		0.43	T
GERP RS		3.7
Varity_R		0.26
gMVP		0.63

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: rs1463790897; hg19: chrX-53222157;