rs59907886
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1BP6_Very_StrongBS1BS2
The ENST00000377270.8(FXN):c.1A>G(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 0.00277 in 1,614,094 control chromosomes in the GnomAD database, including 110 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.015 ( 57 hom., cov: 32)
Exomes 𝑓: 0.0015 ( 53 hom. )
Consequence
FXN
ENST00000377270.8 start_lost
ENST00000377270.8 start_lost
Scores
13
Clinical Significance
Conservation
PhyloP100: 0.704
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 Benign. Variant got -8 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
BP6
?
Variant 9-69046445-A-G is Benign according to our data. Variant chr9-69046445-A-G is described in ClinVar as [Benign]. Clinvar id is 263542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-69046445-A-G is described in Lovd as [Benign].
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0148 (2260/152280) while in subpopulation AFR AF= 0.0507 (2107/41548). AF 95% confidence interval is 0.0489. There are 57 homozygotes in gnomad4. There are 1068 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd at 57 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FXN | NM_000144.5 | c.226A>G | p.Met76Val | missense_variant | 2/5 | ENST00000484259.3 | |
FXN | NM_181425.3 | c.226A>G | p.Met76Val | missense_variant | 2/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FXN | ENST00000484259.3 | c.226A>G | p.Met76Val | missense_variant | 2/5 | 3 | NM_000144.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0148 AC: 2257AN: 152162Hom.: 57 Cov.: 32
GnomAD3 genomes
?
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GnomAD3 exomes AF: 0.00380 AC: 956AN: 251386Hom.: 20 AF XY: 0.00280 AC XY: 380AN XY: 135858
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GnomAD4 exome AF: 0.00151 AC: 2206AN: 1461814Hom.: 53 Cov.: 31 AF XY: 0.00134 AC XY: 976AN XY: 727196
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GnomAD4 genome ? AF: 0.0148 AC: 2260AN: 152280Hom.: 57 Cov.: 32 AF XY: 0.0143 AC XY: 1068AN XY: 74468
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ESP6500AA
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191
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ExAC
?
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546
Asia WGS
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ClinVar
Significance: Benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:4
Benign, criteria provided, single submitter | clinical testing | Invitae | May 08, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | May 04, 2021 | - - |
Likely benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 29, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 18, 2017 | - - |
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 22, 2015 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
DEOGEN2
Benign
T;.;.;T;T;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MetaRNN
Benign
T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;L;L;.;.;.
MutationTaster
Benign
D;N;N;N
PrimateAI
Benign
T
Polyphen
B;B;.;B;.;.;.
Vest4
0.068, 0.085, 0.26
MVP
0.73
MPC
0.30
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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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