17-76733059-CCTCA-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001080510.5(METTL23):c.169_172delCACT(p.His57ValfsTer11) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000094 in 1,606,446 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001080510.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
METTL23 | NM_001080510.5 | c.169_172delCACT | p.His57ValfsTer11 | frameshift_variant | Exon 3 of 5 | ENST00000341249.11 | NP_001073979.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
METTL23 | ENST00000341249.11 | c.169_172delCACT | p.His57ValfsTer11 | frameshift_variant | Exon 3 of 5 | 1 | NM_001080510.5 | ENSP00000341543.5 | ||
ENSG00000267168 | ENST00000587459.1 | c.85_88delCACT | p.His29ValfsTer11 | frameshift_variant | Exon 1 of 2 | 5 | ENSP00000466829.1 |
Frequencies
GnomAD3 genomes AF: 0.0000920 AC: 14AN: 152192Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000930 AC: 22AN: 236608Hom.: 0 AF XY: 0.000125 AC XY: 16AN XY: 128096
GnomAD4 exome AF: 0.0000942 AC: 137AN: 1454254Hom.: 0 AF XY: 0.0000955 AC XY: 69AN XY: 722694
GnomAD4 genome AF: 0.0000920 AC: 14AN: 152192Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74352
ClinVar
Submissions by phenotype
Intellectual disability, autosomal recessive 44 Pathogenic:6
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Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with METTL23-related intellectual disability (MIM#615942). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (26 heterozygotes, 0 homozygotes). (SP) 0702 - Other NMD-predicted variants comparable to the one identified in this case have strong previous evidence for pathogenicity. These variants have been classified as pathogenic, and observed in individuals with METTL23-related intellectual disability (ClinVar, LOVD, PMID: 24626631). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic, and observed in a family with intellectual disability (ClinVar, PMID: 24501276). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has segregated in seven homozygous individuals within a single family (PMID: 24501276). (SP) 1102 - Strong phenotype match for this individual. (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
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not provided Pathogenic:2
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27870114, 24626631, 32552793, 32860008, 37644014, 24501276) -
DNA sequence analysis of the METTL23 gene demonstrated a 4 base pair deletion in exon 3, c.169_172del. This sequence change results in an amino acid frameshift and creates a premature stop codon 10 amino acids downstream of the mutation, p.His57Valfs*11 (NM_001080510.3). This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated METTL23 protein with potentially abnormal function. The METTL23 gene has 10 different transcripts and this sequence change is present in 6 of the 10 transcripts. In the remaining 4 transcripts, the variant falls within a non-coding region. This sequence change was identified in the homozygous state in multiple individuals with intellectual disability and dysmorphic features in a large, consanguineous family of Yemeni origin (PMID: 24501276). The c.169_172del sequence change has been described in the gnomAD database with a population frequency of 0.0097% (dbSNP rs1175461719); however, it has not been observed in the homozygous state in any individuals. These collective evidences indicate that this sequence change is likely pathogenic, however functional studies have not been performed to prove this conclusively. -
Inborn genetic diseases Pathogenic:1
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Intellectual disability Pathogenic:1
PVS1,PP1,PM2 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at