rs104894107

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_000144.5(FXN):ā€‹c.389G>Cā€‹(p.Gly130Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000241 in 1,454,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G130V) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.000024 ( 0 hom. )

Consequence

FXN
NM_000144.5 missense

Scores

11
7
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.30
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
In a chain Frataxin mature form (size 129) in uniprot entity FRDA_HUMAN there are 16 pathogenic changes around while only 2 benign (89%) in NM_000144.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr9-69064942-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3982.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Likely_pathogenic=1, Uncertain_significance=1}.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FXNNM_000144.5 linkuse as main transcriptc.389G>C p.Gly130Ala missense_variant 4/5 ENST00000484259.3
FXNNM_181425.3 linkuse as main transcriptc.389G>C p.Gly130Ala missense_variant 4/5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FXNENST00000484259.3 linkuse as main transcriptc.389G>C p.Gly130Ala missense_variant 4/53 NM_000144.5 P1Q16595-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000358
AC:
9
AN:
251458
Hom.:
0
AF XY:
0.0000589
AC XY:
8
AN XY:
135904
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000229
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000241
AC:
35
AN:
1454046
Hom.:
0
Cov.:
29
AF XY:
0.0000359
AC XY:
26
AN XY:
723994
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000372
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000272
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.0000330
AC:
4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.80
BayesDel_addAF
Pathogenic
0.38
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.98
D;.;.;D;D;D
Eigen
Uncertain
0.67
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
.;D;D;D;.;D
M_CAP
Pathogenic
0.33
D
MetaRNN
Pathogenic
0.97
D;D;D;D;D;D
MetaSVM
Uncertain
0.46
D
MutationAssessor
Pathogenic
3.9
H;H;H;H;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.63
T
PROVEAN
Pathogenic
-5.5
.;D;D;.;.;D
REVEL
Pathogenic
0.97
Sift
Uncertain
0.0020
.;D;D;.;.;D
Sift4G
Uncertain
0.0060
.;D;D;.;.;D
Polyphen
1.0
D;D;.;D;.;.
Vest4
0.97, 0.92, 0.96
MutPred
0.89
Loss of glycosylation at S129 (P = 0.0391);Loss of glycosylation at S129 (P = 0.0391);Loss of glycosylation at S129 (P = 0.0391);Loss of glycosylation at S129 (P = 0.0391);.;.;
MVP
0.97
MPC
1.0
ClinPred
0.98
D
GERP RS
5.5
Varity_R
0.96
gMVP
0.82

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs104894107; hg19: chr9-71679858; API