chr9-69035910-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000144.5(FXN):c.128G>A(p.Arg43His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000035 in 1,486,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R43P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

FXN
NM_000144.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.169

Publications

0 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1041131).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FXN	NM_000144.5 link	c.128G>A	p.Arg43His	missense_variant	Exon 1 of 5	ENST00000484259.3	NP_000135.2
FXN	NM_181425.3 link	c.128G>A	p.Arg43His	missense_variant	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.128G>A	p.Arg43His	missense_variant	Exon 1 of 5	3	NM_000144.5	ENSP00000419243.2
ENSG00000285130	ENST00000642889.1 link	c.128G>A	p.Arg43His	missense_variant	Exon 1 of 25			ENSP00000493780.1

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

151906

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000604

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000223

AC:

AN:

89492

AF XY:

0.0000198

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000549

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000180

AC:

AN:

1334524

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

658026

show subpopulations

African (AFR)

AF:

0.000445

AC:

AN:

26946

American (AMR)

AF:

0.000100

AC:

AN:

29902

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23524

East Asian (EAS)

AF:

0.00

AC:

AN:

30300

South Asian (SAS)

AF:

0.0000403

AC:

AN:

74494

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33078

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3948

European-Non Finnish (NFE)

AF:

9.46e-7

AC:

AN:

1056924

Other (OTH)

AF:

0.0000902

AC:

AN:

55408

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000184

AC:

AN:

151906

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

AN XY:

74202

show subpopulations

African (AFR)

AF:

0.000604

AC:

AN:

41398

American (AMR)

AF:

0.000197

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10562

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67916

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000181

ExAC

AF:

0.0000210

AC:

Asia WGS

AF:

0.000581

AC:

AN:

3456

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 03, 2017

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Nov 14, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.128G>A (p.R43H) alteration is located in exon 1 (coding exon 1) of the FXN gene. This alteration results from a G to A substitution at nucleotide position 128, causing the arginine (R) at amino acid position 43 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.30

T;.;.;T;.;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.60

.;T;T;T;T;T

M_CAP

Pathogenic

0.62

MetaRNN

Benign

0.10

T;T;T;T;T;T

MetaSVM

Uncertain

-0.18

MutationAssessor

Benign

0.55

N;N;N;N;.;.

PhyloP100

-0.17

PrimateAI

Benign

0.46

PROVEAN

Benign

0.31

.;N;N;.;.;.

REVEL

Benign

0.27

Sift

Benign

0.40

.;T;T;.;.;.

Sift4G

Benign

0.27

.;T;T;.;.;.

Polyphen

0.0

B;B;.;B;.;.

Vest4

0.065, 0.091

MutPred

0.49

Loss of MoRF binding (P = 0.0099);Loss of MoRF binding (P = 0.0099);Loss of MoRF binding (P = 0.0099);Loss of MoRF binding (P = 0.0099);Loss of MoRF binding (P = 0.0099);Loss of MoRF binding (P = 0.0099);

MVP

0.56

ClinPred

0.021

GERP RS

-1.4

PromoterAI

-0.0090

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.17

gMVP

0.22

Mutation Taster

=99/1

polymorphism

(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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over