chr9-69064942-G-T
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000144.5(FXN):c.389G>T(p.Gly130Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000417 in 1,606,160 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000144.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FXN | NM_000144.5 | c.389G>T | p.Gly130Val | missense_variant | Exon 4 of 5 | ENST00000484259.3 | NP_000135.2 | |
FXN | NM_181425.3 | c.389G>T | p.Gly130Val | missense_variant | Exon 4 of 5 | NP_852090.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FXN | ENST00000484259.3 | c.389G>T | p.Gly130Val | missense_variant | Exon 4 of 5 | 3 | NM_000144.5 | ENSP00000419243.2 | ||
ENSG00000285130 | ENST00000642889.1 | c.165+28995G>T | intron_variant | Intron 1 of 24 | ENSP00000493780.1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152114Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251458Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135904
GnomAD4 exome AF: 0.0000426 AC: 62AN: 1454046Hom.: 0 Cov.: 29 AF XY: 0.0000428 AC XY: 31AN XY: 723994
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152114Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74296
ClinVar
Submissions by phenotype
not provided Pathogenic:3Uncertain:1
DNA sequence analysis of the FXN gene demonstrated a sequence change, c.389G>T, in exon 4 that results in an amino acid change, p.Gly130Val. The p.Gly130Val change affects a highly conserved amino acid residue located in a domain of the FXN protein that is known to be functional. The p.Gly130Val substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). PMID: 9150176 identified this sequence change in the compound heterozygous state with a GAA trinucleotide repeat expansion in three siblings with atypical Friedreich ataxia phenotype. PMID: 17331979 showed that this sequence change interfered with FXN protein expression in transfected HEK293T cells. This sequence change has been described in the genome Aggregation Database (gnomAD) with a very low population frequency of 0.0063% (dbSNP rs104894107). -
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect with this variant resulting in a protein with a defect in protein processing (PMID: 28812047); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9700204, 11020385, 17331979, 9989622, 26704351, 11030757, 20162437, 26301374, 9150176, 11843702, 26339677, 21298097, 19629184, 19494730, 18537827, 12019217, 10543403, 31980526, 28812047) -
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 11030757, 18537827) 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 Pathogenic:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at