11-85631741-GC-G
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_018480.7(TMEM126B):βc.137delβ(p.Ala46GlufsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,282 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 33)
Exomes π: 0.000027 ( 0 hom. )
Consequence
TMEM126B
NM_018480.7 frameshift
NM_018480.7 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.336
Genes affected
TMEM126B (HGNC:30883): (transmembrane protein 126B) This gene encodes a mitochondrial transmembrane protein which is a component of the mitochondrial complex I assembly complex. The encoded protein serves as an assembly factor that is required for formation of the membrane arm of the complex. It interacts with NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 13. Naturally occurring mutations in this gene are associated with isolated complex I deficiency. A pseudogene of this gene has been defined on chromosome 9. [provided by RefSeq, Apr 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-85631741-GC-G is Pathogenic according to our data. Variant chr11-85631741-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 997635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMEM126B | NM_018480.7 | c.137del | p.Ala46GlufsTer9 | frameshift_variant | 2/5 | ENST00000358867.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMEM126B | ENST00000358867.11 | c.137del | p.Ala46GlufsTer9 | frameshift_variant | 2/5 | 2 | NM_018480.7 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152144Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000160 AC: 40AN: 250608Hom.: 0 AF XY: 0.000155 AC XY: 21AN XY: 135516
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GnomAD4 exome AF: 0.0000267 AC: 39AN: 1461138Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21AN XY: 726900
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152144Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74320
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 17, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 997635). This variant has not been reported in the literature in individuals affected with TMEM126B-related conditions. This variant is present in population databases (rs764565613, gnomAD 0.09%). This sequence change creates a premature translational stop signal (p.Ala46Glufs*9) in the TMEM126B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TMEM126B are known to be pathogenic (PMID: 27374774). - |
Mitochondrial complex 1 deficiency, nuclear type 29 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 20, 2019 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
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