19-5039993-G-T
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2
The NM_015015.3(KDM4B):c.299G>T(p.Arg100Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000869 in 1,611,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000089 ( 0 hom. )
Consequence
KDM4B
NM_015015.3 missense
NM_015015.3 missense
Scores
2
5
12
Clinical Significance
Conservation
PhyloP100: 3.79
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.31179202).
BS2
High AC in GnomAdExome4 at 13 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KDM4B | NM_015015.3 | c.299G>T | p.Arg100Leu | missense_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.299G>T | p.Arg100Leu | missense_variant | 4/23 | 1 | NM_015015.3 | ENSP00000159111.3 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152144Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.00000891 AC: 13AN: 1458992Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2AN XY: 725498
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152144Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74326
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 09, 2024 | Variant summary: KDM4B c.299G>T (p.Arg100Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 247732 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.299G>T in individuals affected with Intellectual Developmental Disorder, Autosomal Dominant 65 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;.;T;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T;T;T;.
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;.;.;L;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
.;.;D;D;D
REVEL
Benign
Sift
Uncertain
.;.;D;D;D
Sift4G
Uncertain
D;T;D;T;D
Polyphen
B;.;.;B;B
Vest4
MVP
MPC
2.3
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at