Variant 1-43690999-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_014663.3(KDM4A):c.2192G>A(p.Gly731Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,614,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KDM4A
NM_014663.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 10.0

Variant links:

Genes affected

KDM4A (HGNC:22978): (lysine demethylase 4A) This gene is a member of the Jumonji domain 2 (JMJD2) family and encodes a protein containing a JmjN domain, a JmjC domain, a JD2H domain, two TUDOR domains, and two PHD-type zinc fingers. This nuclear protein functions as a trimethylation-specific demethylase, converting specific trimethylated histone residues to the dimethylated form, and as a transcriptional repressor. [provided by RefSeq, Apr 2009]

KDM4A links:

ENSG00000284989 (HGNC:):

ENSG00000284989 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.839

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDM4A	NM_014663.3 linkuse as main transcript	c.2192G>A	p.Gly731Asp	missense_variant	14/22	ENST00000372396.4	NP_055478.2	O75164-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KDM4A	ENST00000372396.4 linkuse as main transcript	c.2192G>A	p.Gly731Asp	missense_variant	14/22	1	NM_014663.3	ENSP00000361473.3	O75164-1
ENSG00000284989	ENST00000645057.1 linkuse as main transcript	n.*430G>A		non_coding_transcript_exon_variant	8/26			ENSP00000494063.1	A0A2R8Y4U1
ENSG00000284989	ENST00000645057.1 linkuse as main transcript	n.*430G>A		3_prime_UTR_variant	8/26			ENSP00000494063.1	A0A2R8Y4U1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727246

show subpopulations

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74330

show subpopulations

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:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2024

The c.2192G>A (p.G731D) alteration is located in exon 14 (coding exon 13) of the KDM4A gene. This alteration results from a G to A substitution at nucleotide position 2192, causing the glycine (G) at amino acid position 731 to be replaced by an aspartic acid (D). 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

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.014

MetaRNN

Pathogenic

0.84

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.6

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-5.7

REVEL

Uncertain

0.46

Sift

Benign

0.030

Sift4G

Uncertain

0.049

Polyphen

1.0

Vest4

0.80

MutPred

0.63

Gain of sheet (P = 0.0477);

MVP

0.58

MPC

1.8

ClinPred

0.99

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.70

gMVP

0.77

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over