chr9-69035907-T-G
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_000144.5(FXN):āc.125T>Gā(p.Leu42Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000151 in 1,328,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: not found (cov: 33)
Exomes š: 0.0000015 ( 0 hom. )
Consequence
FXN
NM_000144.5 missense
NM_000144.5 missense
Scores
1
6
7
Clinical Significance
Conservation
PhyloP100: -0.171
Genes affected
FXN (HGNC:3951): (frataxin) This nuclear gene encodes a mitochondrial protein which belongs to the FRATAXIN family. The protein functions in regulating mitochondrial iron transport and respiration. The expansion of intronic trinucleotide repeat GAA from 8-33 repeats to >90 repeats results in Friedreich ataxia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2016]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.37623385).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FXN | NM_000144.5 | c.125T>G | p.Leu42Arg | missense_variant | 1/5 | ENST00000484259.3 | |
FXN | NM_181425.3 | c.125T>G | p.Leu42Arg | missense_variant | 1/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FXN | ENST00000484259.3 | c.125T>G | p.Leu42Arg | missense_variant | 1/5 | 3 | NM_000144.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.00000151 AC: 2AN: 1328170Hom.: 0 Cov.: 35 AF XY: 0.00000153 AC XY: 1AN XY: 654930
GnomAD4 exome
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2
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1328170
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35
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1
AN XY:
654930
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 12, 2023 | Available data are insufficient to determine the clinical significance of the variant at this time. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Computational tools disagree on the variant's effect on normal protein function. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.;D;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L;L;L;.;.
MutationTaster
Benign
N;N;N
PrimateAI
Uncertain
T
Polyphen
D;D;.;D;.;.
Vest4
0.58, 0.64
MutPred
Loss of stability (P = 0.019);Loss of stability (P = 0.019);Loss of stability (P = 0.019);Loss of stability (P = 0.019);Loss of stability (P = 0.019);Loss of stability (P = 0.019);
MVP
0.57
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at