NM_000144.5:c.2T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePS1_ModeratePM2

The NM_000144.5(FXN):​c.2T>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 0.000000736 in 1,358,028 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.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 7.4e-7 ( 0 hom. )

Consequence

FXN
NM_000144.5 start_lost

Scores

8
2
6

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.25
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 Likely_pathogenic. Variant got 6 ACMG points.

PVS1
Start lost variant, next in-frame start position is after 2 pathogenic variants. Next in-frame start position is after 76 codons. Genomic position: 69046445. Lost 0.357 part of the original CDS.
PS1
Another start lost variant in NM_000144.5 (FXN) was described as [Pathogenic] in Lovd
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FXNNM_000144.5 linkc.2T>G p.Met1? start_lost Exon 1 of 5 ENST00000484259.3 NP_000135.2 Q16595-1A0A0S2Z3G4
FXNNM_181425.3 linkc.2T>G p.Met1? start_lost Exon 1 of 5 NP_852090.1 Q16595-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FXNENST00000484259.3 linkc.2T>G p.Met1? start_lost Exon 1 of 5 3 NM_000144.5 ENSP00000419243.2 Q16595-1
ENSG00000285130ENST00000642889.1 linkc.2T>G p.Met1? start_lost Exon 1 of 25 ENSP00000493780.1 A0A2R8YDH4

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
7.36e-7
AC:
1
AN:
1358028
Hom.:
0
Cov.:
29
AF XY:
0.00000149
AC XY:
1
AN XY:
669648
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:
0.0000131
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.43
CADD
Uncertain
24
DANN
Benign
0.96
DEOGEN2
Benign
0.36
T;.;.;T;.;.
Eigen
Benign
-0.11
Eigen_PC
Benign
-0.20
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.90
.;D;D;D;D;D
M_CAP
Pathogenic
0.97
D
MetaRNN
Pathogenic
0.87
D;D;D;D;D;D
MetaSVM
Pathogenic
0.84
D
PROVEAN
Benign
-1.6
.;N;N;.;.;.
REVEL
Pathogenic
0.69
Sift
Pathogenic
0.0
.;D;D;.;.;.
Sift4G
Pathogenic
0.0
.;D;D;.;.;.
Polyphen
0.99
D;D;.;D;.;.
Vest4
0.87, 0.91
MutPred
0.57
Gain of methylation at M1 (P = 0.0176);Gain of methylation at M1 (P = 0.0176);Gain of methylation at M1 (P = 0.0176);Gain of methylation at M1 (P = 0.0176);Gain of methylation at M1 (P = 0.0176);Gain of methylation at M1 (P = 0.0176);
MVP
0.97
ClinPred
0.99
D
GERP RS
1.6
Varity_R
0.93
gMVP
0.54

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-71650700; API