chr11-94998018-C-G

Variant names:

• chr11-94998018-C-G
• NM_018039.3:c.646C>G

Variant summary

Our verdict is Uncertain significance. The variant received 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. Variant has been reported in ClinVar as Uncertain significance (★).

• 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
• Publications: 0 publications found

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]

ENSG00000299693 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

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

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.646C>G	p.Pro216Ala	missense	Exon 3 of 3	NP_060509.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM4D	ENST00000335080.6	TSL:1 MANE Select	c.646C>G	p.Pro216Ala	missense	Exon 3 of 3	ENSP00000334181.5	Q6B0I6
	KDM4D	ENST00000536741.1	TSL:4	c.646C>G	p.Pro216Ala	missense	Exon 2 of 2	ENSP00000460897.1	Q6B0I6
	KDM4D	ENST00000610872.1	TSL:6	c.646C>G	p.Pro216Ala	missense	Exon 1 of 1	ENSP00000482224.1	Q6B0I6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Uncertain	0.17	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.0
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Pathogenic	0.69
Sift	Benign	0.034	D
Sift4G	Uncertain	0.057	T
Polyphen		1.0	D
Vest4		0.40
MutPred		0.92		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
Mutation Taster		=49/51	disease causing

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

Other links and lift over

hg19: chr11-94731182;