rs112921115
Variant summary
Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2
The NM_003482.4(KMT2D):c.3737C>T(p.Thr1246Met) variant causes a missense change. The variant allele was found at a frequency of 0.000653 in 1,613,818 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00065 ( 12 hom. )
Consequence
KMT2D
NM_003482.4 missense
NM_003482.4 missense
Scores
1
7
10
Clinical Significance
Conservation
PhyloP100: 4.56
Genes affected
KMT2D (HGNC:7133): (lysine methyltransferase 2D) The protein encoded by this gene is a histone methyltransferase that methylates the Lys-4 position of histone H3. The encoded protein is part of a large protein complex called ASCOM, which has been shown to be a transcriptional regulator of the beta-globin and estrogen receptor genes. Mutations in this gene have been shown to be a cause of Kabuki syndrome. [provided by RefSeq, Oct 2010]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -15 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, KMT2D
BP4
?
Computational evidence support a benign effect (MetaRNN=0.007923663).
BP6
?
Variant 12-49049851-G-A is Benign according to our data. Variant chr12-49049851-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 309068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49049851-G-A is described in Lovd as [Benign].
BS2
?
High AC in GnomAd at 110 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KMT2D | NM_003482.4 | c.3737C>T | p.Thr1246Met | missense_variant | 12/55 | ENST00000301067.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KMT2D | ENST00000301067.12 | c.3737C>T | p.Thr1246Met | missense_variant | 12/55 | 5 | NM_003482.4 | A2 | |
KMT2D | ENST00000683543.2 | c.3737C>T | p.Thr1246Met | missense_variant | 12/56 | P4 | |||
KMT2D | ENST00000685166.1 | c.3737C>T | p.Thr1246Met | missense_variant | 11/54 | A2 | |||
KMT2D | ENST00000692637.1 | c.3737C>T | p.Thr1246Met | missense_variant | 11/54 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.000723 AC: 110AN: 152204Hom.: 0 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00145 AC: 360AN: 249018Hom.: 4 AF XY: 0.00141 AC XY: 191AN XY: 135122
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GnomAD4 exome AF: 0.000646 AC: 944AN: 1461614Hom.: 12 Cov.: 34 AF XY: 0.000666 AC XY: 484AN XY: 727088
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 21, 2018 | This variant is associated with the following publications: (PMID: 30459467) - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | KMT2D: BS1 - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 13, 2018 | - - |
Kabuki syndrome 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 03, 2021 | - - |
Kabuki syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
KMT2D-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 10, 2019 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Benign
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
D
M_CAP
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Uncertain
D
MutationAssessor
Benign
N
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
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