12-292941-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001042603.3(KDM5A):c.4684A>G(p.Lys1562Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,310 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KDM5A NM_001042603.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.18

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, KDM5A
• BP4: Computational evidence support a benign effect (MetaRNN=0.16834807).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KDM5A	NM_001042603.3	c.4684A>G	p.Lys1562Glu	missense_variant	27/28	ENST00000399788.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KDM5A	ENST00000399788.7	c.4684A>G	p.Lys1562Glu	missense_variant	27/28	1	NM_001042603.3	P1
KDM5A	ENST00000540838.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000803 AC: 2 AN: 248938 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135082

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461310 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726968

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2022

The c.4684A>G (p.K1562E) alteration is located in exon 27 (coding exon 27) of the KDM5A gene. This alteration results from a A to G substitution at nucleotide position 4684, causing the lysine (K) at amino acid position 1562 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.068	T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	-0.084	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	0.83	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.28	N
REVEL	Uncertain	0.34
Sift	Benign	0.33	T
Sift4G	Benign	0.60	T
Polyphen		0.39	B
Vest4		0.30
MutPred		0.23		Loss of methylation at K1562 (P = 0.0153);
MVP		0.48
MPC		0.80
ClinPred		0.25	T
GERP RS		5.6
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.12
gMVP		0.064

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: rs765603943; hg19: chr12-402107;