Genetic Variant NM_018039.3:c.1148G>A (chr11-94998520-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_018039.3(KDM4D):c.1148G>A(p.Arg383Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,612,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R383W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

KDM4D
NM_018039.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.18

Publications

0 publications found

Variant links:

Genes affected

KDM4D (HGNC:25498): (lysine demethylase 4D) Enables histone H3-methyl-lysine-9 demethylase activity. Involved in histone H3-K9 demethylation. Acts upstream of or within several processes, including cellular response to ionizing radiation; positive regulation of chromatin binding activity; and positive regulation of double-strand break repair via nonhomologous end joining. Located in site of double-strand break. Biomarker of nephroblastoma. [provided by Alliance of Genome Resources, Apr 2022]

KDM4D links:

ENSG00000299693 (HGNC:):

ENSG00000299693 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.033431828).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018039.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM4D	NM_018039.3	MANE Select	c.1148G>A	p.Arg383Gln	missense	Exon 3 of 3	NP_060509.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KDM4D	ENST00000335080.6	TSL:1 MANE Select	c.1148G>A	p.Arg383Gln	missense	Exon 3 of 3	ENSP00000334181.5	Q6B0I6
KDM4D	ENST00000536741.1	TSL:4	c.1148G>A	p.Arg383Gln	missense	Exon 2 of 2	ENSP00000460897.1	Q6B0I6
KDM4D	ENST00000610872.1	TSL:6	c.1148G>A	p.Arg383Gln	missense	Exon 1 of 1	ENSP00000482224.1	Q6B0I6

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000360

AC:

AN:

249678

AF XY:

0.0000370

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000158

AC:

AN:

1460256

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726488

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51838

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000719

AC:

AN:

1111986

Other (OTH)

AF:

0.0000497

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000105

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41538

American (AMR)

AF:

0.0000654

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000581

Hom.:

Bravo

AF:

0.0000907

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.30

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.038

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.42

M_CAP

Benign

0.0045

MetaRNN

Benign

0.033

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

PhyloP100

-1.2

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.69

REVEL

Benign

0.0090

Sift

Benign

0.36

Sift4G

Benign

0.41

Polyphen

0.015

Vest4

0.081

MVP

0.11

MPC

0.67

ClinPred

0.058

GERP RS

-4.6

Varity_R

0.017

gMVP

0.14

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over