Variant 11-94998375-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000335080.6(KDM4D):c.1003C>G(p.Leu335Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,614,064 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

KDM4D
ENST00000335080.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.844

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17501122).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDM4D	NM_018039.3 linkuse as main transcript	c.1003C>G	p.Leu335Val	missense_variant	3/3	ENST00000335080.6	NP_060509.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
KDM4D	ENST00000335080.6 linkuse as main transcript	c.1003C>G	p.Leu335Val	missense_variant	3/3	1	NM_018039.3	ENSP00000334181	P1
KDM4D	ENST00000536741.1 linkuse as main transcript	c.1003C>G	p.Leu335Val	missense_variant	2/2	4		ENSP00000460897	P1
KDM4D	ENST00000610872.1 linkuse as main transcript	c.1003C>G	p.Leu335Val	missense_variant	1/1			ENSP00000482224	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152202

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

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251378

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135852

show subpopulations

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:

0.0000440

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727228

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:

0.0000171

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74362

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

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

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

Oct 27, 2022

The c.1003C>G (p.L335V) alteration is located in exon 3 (coding exon 1) of the KDM4D gene. This alteration results from a C to G substitution at nucleotide position 1003, causing the leucine (L) at amino acid position 335 to be replaced by a valine (V). 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

0.098

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

T;T;T

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

.;.;D

M_CAP

Benign

0.0092

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

3.1

M;M;M

MutationTaster

Benign

0.64

N;N

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.4

N;.;.

REVEL

Benign

0.026

Sift

Uncertain

0.011

D;.;.

Sift4G

Uncertain

0.046

D;D;D

Polyphen

0.34

B;B;B

Vest4

0.13

MutPred

0.45

Gain of methylation at K337 (P = 0.0587);Gain of methylation at K337 (P = 0.0587);Gain of methylation at K337 (P = 0.0587);

MVP

0.32

MPC

0.88

ClinPred

0.48

GERP RS

1.8

Varity_R

0.32

gMVP

0.83

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