Genetic Variant KDM4D:p.Ile327Val (chr11-94998351-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_018039.3(KDM4D):c.979A>G(p.Ile327Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

KDM4D
NM_018039.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.594

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.048723638).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDM4D	NM_018039.3 link	c.979A>G	p.Ile327Val	missense_variant	Exon 3 of 3	ENST00000335080.6	NP_060509.2	Q6B0I6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KDM4D	ENST00000335080.6 link	c.979A>G	p.Ile327Val	missense_variant	Exon 3 of 3	1	NM_018039.3	ENSP00000334181.5	Q6B0I6
KDM4D	ENST00000536741.1 link	c.979A>G	p.Ile327Val	missense_variant	Exon 2 of 2	4		ENSP00000460897.1	Q6B0I6
KDM4D	ENST00000610872.1 link	c.979A>G	p.Ile327Val	missense_variant	Exon 1 of 1	6		ENSP00000482224.1	Q6B0I6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251380

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135856

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000150

AC:

AN:

1461856

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727226

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:

0.0000180

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.979A>G (p.I327V) alteration is located in exon 3 (coding exon 1) of the KDM4D gene. This alteration results from a A to G substitution at nucleotide position 979, causing the isoleucine (I) at amino acid position 327 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

0.12

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Benign

0.49

DEOGEN2

Benign

0.041

T;T;T

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.76

.;.;T

M_CAP

Benign

0.0030

MetaRNN

Benign

0.049

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

L;L;L

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.61

N;.;.

REVEL

Benign

0.015

Sift

Benign

0.47

T;.;.

Sift4G

Benign

0.87

T;T;T

Polyphen

0.010

B;B;B

Vest4

0.11

MutPred

0.39

Loss of catalytic residue at I327 (P = 0.0803);Loss of catalytic residue at I327 (P = 0.0803);Loss of catalytic residue at I327 (P = 0.0803);

MVP

0.20

MPC

0.50

ClinPred

0.044

GERP RS

-0.20

Varity_R

0.12

gMVP

0.80

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