9-69035785-G-T

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong

The NM_000144.5(FXN):c.3G>T(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 0.00000464 in 1,509,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000037 ( 0 hom. )

Consequence

FXN
NM_000144.5 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 2.80

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]

FXN links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 20 ACMG points.

PVS1

Start lost variant, no new inframe start found.

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;

PP5

Variant 9-69035785-G-T is Pathogenic according to our data. Variant chr9-69035785-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 3983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-69035785-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FXN	NM_000144.5 linkuse as main transcript	c.3G>T	p.Met1?	start_lost	1/5	ENST00000484259.3
FXN	NM_181425.3 linkuse as main transcript	c.3G>T	p.Met1?	start_lost	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FXN	ENST00000484259.3 linkuse as main transcript	c.3G>T	p.Met1?	start_lost	1/5	3	NM_000144.5	P1	Q16595-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000913

AC:

AN:

109492

Hom.:

AF XY:

0.0000165

AC XY:

AN XY:

60612

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000243

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000368

AC:

AN:

1357716

Hom.:

Cov.:

AF XY:

0.00000598

AC XY:

AN XY:

669456

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:

0.00000468

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000435

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000506

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 24, 2022	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant results in the loss of the initiator methionine codon and is predicted to interfere with protein translation. This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Friedreich ataxia 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 12, 2022

The c.3G>T (p.Met1?) variant in FXN has been reported in five individuals with Friedreich ataxia who are compound heterozygous with a pathogenic GAA repeat expansion and segregated with disease in one affected individual from one family (Cossee 1997 PMID: 9090376, Zuhlke 1998 PMID: 9737785). It has also been identified 0.002% (1/41092) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar as pathogenic (Variation ID 3983). This variant affects the translation initiation start codon (ATG) and is predicted to lead to a shortened protein that is <75% of the length of the full protein. Multiple additional variants with the same effect (p.Met1?) have been reported with pathogenic GAA repeat expansions in individuals with Friedreich ataxia (Cossee 1999 PMID: 9989622, Potter 2000 PMID: 10913738). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Friedreich ataxia. ACMG/AMP Criteria applied: PM3_VeryStrong, PM1, PVS1_Moderate, PM2_Supporting, PP1. -

Friedreich ataxia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.51

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Benign

0.37

T;.;.;T;.;.

Eigen

Benign

0.10

Eigen_PC

Benign

0.018

FATHMM_MKL

Uncertain

0.91

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.87

D;D;D;D;D;D

MetaSVM

Pathogenic

0.96

MutationTaster

Benign

1.0

D;D;D

Polyphen

0.92

P;P;.;P;.;.

Vest4

0.84, 0.90

MutPred

0.59

Loss of disorder (P = 0.0292);Loss of disorder (P = 0.0292);Loss of disorder (P = 0.0292);Loss of disorder (P = 0.0292);Loss of disorder (P = 0.0292);Loss of disorder (P = 0.0292);

MVP

0.99

ClinPred

0.99

GERP RS

2.8

Varity_R

0.97

gMVP

0.35

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over