1-43691034-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_014663.3(KDM4A):​c.2227G>A​(p.Val743Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000217 in 1,613,964 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: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

KDM4A
NM_014663.3 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.67
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-AS1 (HGNC:40528): (KDM4A antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.15501562).
BS2
High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KDM4ANM_014663.3 linkc.2227G>A p.Val743Ile missense_variant 14/22 ENST00000372396.4 NP_055478.2 O75164-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KDM4AENST00000372396.4 linkc.2227G>A p.Val743Ile missense_variant 14/221 NM_014663.3 ENSP00000361473.3 O75164-1
ENSG00000284989ENST00000645057.1 linkn.*465G>A non_coding_transcript_exon_variant 8/26 ENSP00000494063.1 A0A2R8Y4U1
ENSG00000284989ENST00000645057.1 linkn.*465G>A 3_prime_UTR_variant 8/26 ENSP00000494063.1 A0A2R8Y4U1

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152170
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.00143
GnomAD3 exomes
AF:
0.0000279
AC:
7
AN:
251332
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135834
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.0000867
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:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000185
AC:
27
AN:
1461794
Hom.:
0
Cov.:
31
AF XY:
0.0000179
AC XY:
13
AN XY:
727206
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.0000894
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:
0.0000126
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152170
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74332
show subpopulations
Gnomad4 AFR
AF:
0.0000724
Gnomad4 AMR
AF:
0.0000654
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:
0.00143
Alfa
AF:
0.00000555
Hom.:
0
Bravo
AF:
0.0000567
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

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 submitterclinical testingAmbry GeneticsMay 21, 2024The c.2227G>A (p.V743I) 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 2227, causing the valine (V) at amino acid position 743 to be replaced by an isoleucine (I). 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
Benign
0.12
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.47
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.015
T
Eigen
Benign
0.12
Eigen_PC
Uncertain
0.25
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.94
D
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.16
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.35
N
PrimateAI
Uncertain
0.51
T
PROVEAN
Benign
-0.010
N
REVEL
Benign
0.10
Sift
Benign
0.092
T
Sift4G
Benign
0.20
T
Polyphen
0.42
B
Vest4
0.18
MVP
0.24
MPC
1.4
ClinPred
0.20
T
GERP RS
5.0
Varity_R
0.062
gMVP
0.48

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.

Other links and lift over

dbSNP: rs144765200; hg19: chr1-44156705; API