rs398124308
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_017547.4(FOXRED1):c.612_615dupAGTG(p.Ala206SerfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000311 in 1,613,142 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_017547.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000131 AC: 20AN: 152158Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000227 AC: 57AN: 251338Hom.: 0 AF XY: 0.000206 AC XY: 28AN XY: 135890
GnomAD4 exome AF: 0.000330 AC: 482AN: 1460866Hom.: 0 Cov.: 30 AF XY: 0.000282 AC XY: 205AN XY: 726824
GnomAD4 genome AF: 0.000131 AC: 20AN: 152276Hom.: 0 Cov.: 31 AF XY: 0.000107 AC XY: 8AN XY: 74468
ClinVar
Submissions by phenotype
Mitochondrial complex 1 deficiency, nuclear type 19 Pathogenic:6
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This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5. -
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not provided Pathogenic:5
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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: 22200994, 30956948, 31589614, 33613441, 30723688, 31065540, 37846277) -
This sequence change creates a premature translational stop signal (p.Ala206Serfs*15) in the FOXRED1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FOXRED1 are known to be pathogenic (PMID: 20818383, 20858599). This variant is present in population databases (rs765593341, gnomAD 0.07%). This premature translational stop signal has been observed in individuals with mitochondrial complex I deficiency (PMID: 22200994, 31065540). ClinVar contains an entry for this variant (Variation ID: 95754). For these reasons, this variant has been classified as Pathogenic. -
Leigh syndrome Pathogenic:1
Variant summary: The FOXRED1 c.612_615dupAGTG (p.Ala206Serfs) variant results in a premature termination codon, predicted to cause a truncated or absent FOXRED1 protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. If NMD is escaped, this variant is predicted to truncate Glycine/D-amino acid oxidase domain. Truncation downstream of this position has also been reported (PMID: 20818383). This variant was found in 24/120958 control chromosomes at a frequency of 0.0001984, which does not exceed the estimated maximal expected allele frequency of a pathogenic FOXRED1 variant (0.00125). This variant has been reported in literature in one patient with mitochondrial complex I deficiency in compound heterozygous state with p.R136W variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as Pathogenic. -
Mitochondrial complex I deficiency Pathogenic:1
The Ala206SerfsX15 variant has been identified in 0.012% (1/8254) of European American chromosomes and 0.023% (1/4264) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). The same frameshift variant (but from a different nucleotide variant) in FOXRED1 has been reported in 1 individual with mitochondrial complex I deficiency (Haack 2012). This individual was compound heterozygous. The Ala206SerfsX15 frameshift variant is predicted to alter the protein’s amino acid sequence beginning at position 206 and lead to a premature termination codon 15 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant is likely to be pathogenic, though additional data are required to fully establish the role of the FOXRED1 gene in disease given limited studies to date. -
Inborn genetic diseases Pathogenic:1
The c.612_615dupAGTG (p.A206Sfs*15) alteration, located in exon 5 (coding exon 5) of the FOXRED1 gene, consists of a duplication of AGTG at position 612, causing a translational frameshift with a predicted alternate stop codon after 15 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration has been detected with another mutation in patients with FOXRED1-related mitochondrial complex I deficiency (Ahmed, 2017; Apatean, 2019; Haack, 2012). Based on the available evidence, this alteration is classified as pathogenic. -
Mitochondrial complex I deficiency, nuclear type 1 Pathogenic:1
The c.612_615dup;p.(Ala206Serfs*15) is a null frameshift variant (NMD) in the FOXRED1 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevantexon to the transcript -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 95754; PMID: 33613441; 31065540; 22200994; 30723688; 30956948; 31589614) - PS4. The variant is present at low allele frequencies population databases (rs398124308– gnomAD 0.01314%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Ala206Serfs*15) was detected in trans with a pathogenic variant(PMID: 22200994, 30723688, 31065540) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at