rs59907886

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000144.5(FXN):​c.226A>C​(p.Met76Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign 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. M76V) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

FXN
NM_000144.5 missense

Scores

19

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.704
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 Uncertain_significance. Variant got 2 ACMG points.

PM1
In a chain Frataxin(56-210) (size 154) in uniprot entity FRDA_HUMAN there are 8 pathogenic changes around while only 2 benign (80%) in NM_000144.5
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.20953521).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FXNNM_000144.5 linkc.226A>C p.Met76Leu missense_variant Exon 2 of 5 ENST00000484259.3 NP_000135.2 Q16595-1A0A0S2Z3G4
FXNNM_181425.3 linkc.226A>C p.Met76Leu missense_variant Exon 2 of 5 NP_852090.1 Q16595-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FXNENST00000484259.3 linkc.226A>C p.Met76Leu missense_variant Exon 2 of 5 3 NM_000144.5 ENSP00000419243.2 Q16595-1
ENSG00000285130ENST00000642889.1 linkc.165+10498A>C intron_variant Intron 1 of 24 ENSP00000493780.1 A0A2R8YDH4

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461814
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727196
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.016
T
BayesDel_noAF
Benign
-0.26
CADD
Benign
14
DANN
Benign
0.60
DEOGEN2
Benign
0.31
T;.;.;T;T;T;.
Eigen
Benign
-0.42
Eigen_PC
Benign
-0.52
FATHMM_MKL
Benign
0.24
N
LIST_S2
Benign
0.54
.;T;T;T;.;D;T
M_CAP
Benign
0.033
D
MetaRNN
Benign
0.12
T;T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.9
L;L;L;L;.;.;.
PrimateAI
Benign
0.35
T
PROVEAN
Benign
-0.58
.;N;N;.;N;N;.
REVEL
Benign
0.15
Sift
Benign
0.45
.;T;T;.;D;T;.
Sift4G
Benign
0.82
.;T;T;.;.;T;.
Polyphen
0.0010
B;B;.;B;.;.;.
Vest4
0.14, 0.17, 0.36
MutPred
0.43
Loss of MoRF binding (P = 0.0784);Loss of MoRF binding (P = 0.0784);Loss of MoRF binding (P = 0.0784);Loss of MoRF binding (P = 0.0784);.;.;Loss of MoRF binding (P = 0.0784);
MVP
0.74
MPC
0.28
ClinPred
0.032
T
GERP RS
1.1
Varity_R
0.14
gMVP
0.31

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-71661361; API