12-295745-C-A

Position:

• chr12-295745-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3 PP5_Moderate

The ENST00000399788.7(KDM5A):​c.4283G>T​(p.Arg1428Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: KDM5A ENST00000399788.7 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.60

Genes affected

KDM5A (HGNC:9886): (lysine demethylase 5A) This gene encodes a member of the Jumonji, AT-rich interactive domain 1 (JARID1) histone demethylase protein family. The encoded protein plays a role in gene regulation through the histone code by specifically demethylating lysine 4 of histone H3. The encoded protein interacts with many other proteins, including retinoblastoma protein, and is implicated in the transcriptional regulation of Hox genes and cytokines. This gene may play a role in tumor progression. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KDM5A. . Gene score misZ 2.2471 (greater than the threshold 3.09). Trascript score misZ 3.5946 (greater than threshold 3.09). GenCC has associacion of gene with congenital heart disease.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.757
• PP5: Variant 12-295745-C-A is Pathogenic according to our data. Variant chr12-295745-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2500344.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDM5A	NM_001042603.3	c.4283G>T	p.Arg1428Leu	missense_variant	26/28	ENST00000399788.7	NP_001036068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KDM5A	ENST00000399788.7	c.4283G>T	p.Arg1428Leu	missense_variant	26/28	1	NM_001042603.3	ENSP00000382688	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Seizure;C3714756:Intellectual disability Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Institute of Human Genetics, University of Leipzig Medical Center

Mar 02, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.95	N
REVEL	Uncertain	0.55
Sift	Uncertain	0.010	D
Sift4G	Benign	0.29	T
Polyphen		0.99	D
Vest4		0.77
MutPred		0.32		Loss of solvent accessibility (P = 3e-04);
MVP		0.70
MPC		0.23
ClinPred		0.80	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.21
gMVP		0.56

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-404911;