19-5033003-A-G

Position:

• chr19-5033003-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015015.3(KDM4B):​c.113A>G​(p.Gln38Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,574 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• 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]

KDM4B (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDM4B	NM_015015.3	c.113A>G	p.Gln38Arg	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.113A>G	p.Gln38Arg	missense_variant	3/23	1	NM_015015.3	ENSP00000159111.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461574 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727098

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

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

Jun 04, 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	Benign	0.21
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.034	T;.;T;.;T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.89	D;D;D;D;.
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.58	D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	.;.;.;L;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.0	.;.;D;D;D
REVEL	Uncertain	0.39
Sift	Benign	0.030	.;.;D;T;T
Sift4G	Benign	0.070	T;T;T;T;T
Polyphen		0.12	B;.;.;B;B
Vest4		0.83
MutPred		0.57		Gain of methylation at Q38 (P = 0.0136);Gain of methylation at Q38 (P = 0.0136);Gain of methylation at Q38 (P = 0.0136);Gain of methylation at Q38 (P = 0.0136);Gain of methylation at Q38 (P = 0.0136);
MVP		0.70
MPC		1.7
ClinPred		0.97	D
GERP RS		4.7
gMVP		0.94

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: chr19-5033014;