dbSNP rs104894108: FXN:p.Met1? (chr9-69035785-G-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_StrongPS1_ModeratePM2

The NM_000144.5(FXN):c.3G>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FXN
NM_000144.5 start_lost

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.80

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

Friedreich ataxia
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Friedreich ataxia 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
Friedreich ataxia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

FXN links:

ENSG00000285130 (HGNC:):

ENSG00000285130 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 5 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 ClinVar

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FXN	NM_000144.5 link	c.3G>A	p.Met1?	start_lost	Exon 1 of 5	ENST00000484259.3	NP_000135.2
FXN	NM_181425.3 link	c.3G>A	p.Met1?	start_lost	Exon 1 of 5		NP_852090.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FXN	ENST00000484259.3 link	c.3G>A	p.Met1?	start_lost	Exon 1 of 5	3	NM_000144.5	ENSP00000419243.2
ENSG00000285130	ENST00000642889.1 link	c.3G>A	p.Met1?	start_lost	Exon 1 of 25			ENSP00000493780.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1357714

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

669456

African (AFR)

AF:

0.00

AC:

AN:

28542

American (AMR)

AF:

0.00

AC:

AN:

33746

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24354

East Asian (EAS)

AF:

0.00

AC:

AN:

33284

South Asian (SAS)

AF:

0.00

AC:

AN:

76302

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32916

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4012

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1067832

Other (OTH)

AF:

0.00

AC:

AN:

56726

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.51

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.37

T;.;.;T;.;.

Eigen

Benign

0.10

Eigen_PC

Benign

0.018

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.90

.;D;D;D;D;D

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.89

D;D;D;D;D;D

MetaSVM

Pathogenic

0.96

PhyloP100

2.8

PROVEAN

Benign

-1.3

.;N;N;.;.;.

REVEL

Pathogenic

0.70

Sift

Pathogenic

0.0

.;D;D;.;.;.

Sift4G

Pathogenic

0.0

.;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

PromoterAI

0.069

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.97

gMVP

0.35

Mutation Taster

=3/197

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over