9-69035785-G-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_ModeratePS1_ModeratePM2PP5_Very_Strong
The NM_000144.5(FXN):c.3G>T(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000464 in 1,509,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000144.5 start_lost
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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FXN | NM_000144.5 | c.3G>T | p.Met1? | start_lost | Exon 1 of 5 | ENST00000484259.3 | NP_000135.2 | |
FXN | NM_181425.3 | c.3G>T | p.Met1? | start_lost | Exon 1 of 5 | NP_852090.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FXN | ENST00000484259.3 | c.3G>T | p.Met1? | start_lost | Exon 1 of 5 | 3 | NM_000144.5 | ENSP00000419243.2 | ||
ENSG00000285130 | ENST00000642889.1 | c.3G>T | p.Met1? | start_lost | Exon 1 of 25 | ENSP00000493780.1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152180Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000913 AC: 1AN: 109492Hom.: 0 AF XY: 0.0000165 AC XY: 1AN XY: 60612
GnomAD4 exome AF: 0.00000368 AC: 5AN: 1357716Hom.: 0 Cov.: 29 AF XY: 0.00000598 AC XY: 4AN XY: 669456
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152180Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74340
ClinVar
Submissions by phenotype
not provided Pathogenic:3
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The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant results in the loss of the initiator methionine codon and is predicted to interfere with protein translation. This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. -
Friedreich ataxia 1 Pathogenic:1
The c.3G>T (p.Met1?) variant in FXN has been reported in five individuals with Friedreich ataxia who are compound heterozygous with a pathogenic GAA repeat expansion and segregated with disease in one affected individual from one family (Cossee 1997 PMID: 9090376, Zuhlke 1998 PMID: 9737785). It has also been identified 0.002% (1/41092) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar as pathogenic (Variation ID 3983). This variant affects the translation initiation start codon (ATG) and is predicted to lead to a shortened protein that is <75% of the length of the full protein. Multiple additional variants with the same effect (p.Met1?) have been reported with pathogenic GAA repeat expansions in individuals with Friedreich ataxia (Cossee 1999 PMID: 9989622, Potter 2000 PMID: 10913738). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Friedreich ataxia. ACMG/AMP Criteria applied: PM3_VeryStrong, PM1, PVS1_Moderate, PM2_Supporting, PP1. -
Friedreich ataxia Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at