19-5039838-C-G

Position:

• chr19-5039838-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015015.3(KDM4B):​c.144C>G​(p.Ile48Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KDM4B NM_015015.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.35

Genes affected

KDM4B (HGNC:29136): (lysine demethylase 4B) Enables histone H3-methyl-lysine-36 demethylase activity and histone H3-methyl-lysine-9 demethylase activity. Involved in histone H3-K36 demethylation and histone H3-K9 demethylation. Located in cytosol and nucleoplasm. Implicated in autosomal dominant non-syndromic intellectual disability; breast cancer; colorectal cancer; malignant peripheral nerve sheath tumor; and stomach cancer. Biomarker of several diseases, including alopecia areata; lung cancer; medulloblastoma; prostate cancer; and stomach cancer. [provided by Alliance of Genome Resources, Apr 2022]

KDM4B (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.42355028).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDM4B	NM_015015.3	c.144C>G	p.Ile48Met	missense_variant, splice_region_variant	4/23	ENST00000159111.9	NP_055830.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KDM4B	ENST00000159111.9	c.144C>G	p.Ile48Met	missense_variant, splice_region_variant	4/23	1	NM_015015.3	ENSP00000159111.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 09, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;.;T;.;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.95	D;D;D;D;.
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.42	T;T;T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.0	.;.;.;M;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.0	.;.;N;N;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0010	.;.;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		0.97	D;.;.;P;D
Vest4		0.64
MutPred		0.70		Gain of catalytic residue at I48 (P = 0.0245);Gain of catalytic residue at I48 (P = 0.0245);Gain of catalytic residue at I48 (P = 0.0245);Gain of catalytic residue at I48 (P = 0.0245);Gain of catalytic residue at I48 (P = 0.0245);
MVP		0.29
MPC		2.5
ClinPred		0.90	D
GERP RS		1.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
gMVP		0.96

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: chr19-5039849;