11-94998018-C-G

Position:

• chr11-94998018-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_018039.3(KDM4D):​c.646C>G​(p.Pro216Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KDM4D NM_018039.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.04

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDM4D	NM_018039.3	c.646C>G	p.Pro216Ala	missense_variant	3/3	ENST00000335080.6	NP_060509.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KDM4D	ENST00000335080.6	c.646C>G	p.Pro216Ala	missense_variant	3/3	1	NM_018039.3	ENSP00000334181.5
KDM4D	ENST00000536741.1	c.646C>G	p.Pro216Ala	missense_variant	2/2	4		ENSP00000460897.1
KDM4D	ENST00000610872.1	c.646C>G	p.Pro216Ala	missense_variant	1/1	6		ENSP00000482224.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2024

The c.646C>G (p.P216A) 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 646, causing the proline (P) at amino acid position 216 to be replaced by an alanine (A). 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	0.21
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T;T;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	.;.;D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Uncertain	2.4	M;M;M
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-7.6	D;.;.
REVEL	Pathogenic	0.69
Sift	Benign	0.034	D;.;.
Sift4G	Uncertain	0.057	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.40
MutPred		0.92		Loss of catalytic residue at P216 (P = 0.0139);Loss of catalytic residue at P216 (P = 0.0139);Loss of catalytic residue at P216 (P = 0.0139);
MVP		0.79
MPC		1.5
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.75
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-94731182;