rs573006534
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_018480.7(TMEM126B):c.397G>A(p.Asp133Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,609,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_018480.7 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMEM126B | NM_018480.7 | c.397G>A | p.Asp133Asn | missense_variant, splice_region_variant | 3/5 | ENST00000358867.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMEM126B | ENST00000358867.11 | c.397G>A | p.Asp133Asn | missense_variant, splice_region_variant | 3/5 | 2 | NM_018480.7 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000789 AC: 12AN: 152094Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000844 AC: 21AN: 248690Hom.: 0 AF XY: 0.0000744 AC XY: 10AN XY: 134352
GnomAD4 exome AF: 0.000123 AC: 180AN: 1457772Hom.: 0 Cov.: 30 AF XY: 0.000121 AC XY: 88AN XY: 725232
GnomAD4 genome AF: 0.0000788 AC: 12AN: 152212Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6AN XY: 74442
ClinVar
Submissions by phenotype
Mitochondrial complex 1 deficiency, nuclear type 29 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 19, 2022 | Variant summary: TMEM126B c.397G>A (p.Asp133Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Two predict the variant weakens a 5' donor site and one predicts the variant abolishes a 5 splicing donor site. Experimental evidence supports these predictions demonstrating the variant affects mRNA splicing leading to the utilization of an alternative splice site, which generated a truncated cDNA lacking 104 bp from exon 3 (Sanchez-Caballero_2016). The variant allele was found at a frequency of 8.4e-05 in 248690 control chromosomes (gnomAD). c.397G>A has been reported in the literature in two compound heterozygous individuals affected with Mitochondrial Complex 1 Deficiency (Sanchez-Caballero_2016). These data indicate that the variant is likely to be associated with disease. A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 13, 2018 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 14, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 27374773, 35160083) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at