19-5033012-A-G

Position:

• chr19-5033012-A-G

Variant summary

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

The NM_015015.3(KDM4B):​c.122A>G​(p.His41Arg) variant causes a missense change involving the alteration of a 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: 33)
• Consequence: KDM4B NM_015015.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.27

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]

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, 0.916

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDM4B	NM_015015.3	c.122A>G	p.His41Arg	missense_variant	3/23	ENST00000159111.9	NP_055830.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KDM4B	ENST00000159111.9	c.122A>G	p.His41Arg	missense_variant	3/23	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

Jan 10, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on 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	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.;T;.;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D;D;.
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.9	.;.;.;M;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-7.4	.;.;D;D;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0010	.;.;D;D;D
Sift4G	Uncertain	0.011	D;D;D;D;D
Polyphen		0.99	D;.;.;D;D
Vest4		0.83
MutPred		0.80		Gain of MoRF binding (P = 0.0468);Gain of MoRF binding (P = 0.0468);Gain of MoRF binding (P = 0.0468);Gain of MoRF binding (P = 0.0468);Gain of MoRF binding (P = 0.0468);
MVP		0.65
MPC		2.7
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
gMVP		0.92

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: chr19-5033023;