17-76733165-TACC-T
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4_SupportingPP5
The NM_001080510.5(METTL23):c.278_280del(p.Pro93del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,613,966 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00016 ( 0 hom. )
Consequence
METTL23
NM_001080510.5 inframe_deletion
NM_001080510.5 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.55
Genes affected
METTL23 (HGNC:26988): (methyltransferase 23, arginine) The protein encoded by this gene functions as a transcription factor regulator in the transcriptional pathway for human cognition. It is a partner of the alpha subunit of the GA-binding protein transcription factor. Mutations in this gene cause mild autosomal recessive intellectual disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_001080510.5. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant 17-76733165-TACC-T is Pathogenic according to our data. Variant chr17-76733165-TACC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 520855.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| METTL23 | NM_001080510.5 | c.278_280del | p.Pro93del | inframe_deletion | 3/5 | ENST00000341249.11 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| METTL23 | ENST00000341249.11 | c.278_280del | p.Pro93del | inframe_deletion | 3/5 | 1 | NM_001080510.5 | P1 |
Frequencies
GnomAD3 genomes 0.000131 AC: 20AN: 152244Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000100 AC: 25AN: 248960Hom.: 0 AF XY: 0.0000962 AC XY: 13AN XY: 135076
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GnomAD4 exome AF: 0.000156 AC: 228AN: 1461604Hom.: 0 AF XY: 0.000166 AC XY: 121AN XY: 727062
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GnomAD4 genome 0.000131 AC: 20AN: 152362Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11AN XY: 74510
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2022 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 06, 2023 | In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Inborn genetic diseases Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 10, 2023 | The c.278_280delCAC (p.P93del) alteration, located in exon 3 (coding exon 2) of the METTL23 gene, results from an in-frame deletion at nucleotide positions c.278 to c.280. This results in the deletion of a proline residue at codon 93. Based on data from gnomAD, this allele has an overall frequency of 0.010% (28/280370) total alleles studied. The highest observed frequency was 0.025% (6/24172) of African alleles. This amino acid position is not well conserved in available vertebrate species. The p.P93 amino acid is located in the lysine methyltransferase domain of the METTL23 protein. Methyltransferases catalyze the transfer of a methyl group from S-adenosyl L-methionine (SAM) to a nucleophilic acceptor (Kozbial, 2005). All methyltransferases share a conserved region of approximately 130 amino acids, which allows them to bind to SAM (Schluckebier, 1995). This alteration is predicted to be deleterious by in silico analysis (Choi, 2012). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Intellectual disability, autosomal recessive 44 Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Apr 13, 2023 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at