NM_000144.5:c.118C>T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3BS1_Supporting

The NM_000144.5(FXN):c.118C>T(p.Arg40Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000662 in 1,487,292 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R40H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00069 ( 1 hom. )

Consequence

FXN
NM_000144.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 0.0210

Publications

3 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: Labcorp Genetics (formerly Invitae), G2P
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: Uncertain_significance. The variant received 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.793

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000692 (924/1335348) while in subpopulation NFE AF = 0.000842 (890/1057314). AF 95% confidence interval is 0.000795. There are 1 homozygotes in GnomAdExome4. There are 440 alleles in the male GnomAdExome4 subpopulation. Median coverage is 36. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000144.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FXN	NM_000144.5	MANE Select	c.118C>T	p.Arg40Cys	missense	Exon 1 of 5	NP_000135.2
	FXN	NM_181425.3		c.118C>T	p.Arg40Cys	missense	Exon 1 of 5	NP_852090.1	Q16595-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FXN	ENST00000484259.3	TSL:3 MANE Select	c.118C>T	p.Arg40Cys	missense	Exon 1 of 5	ENSP00000419243.2	Q16595-1
ENSG00000285130	ENST00000642889.1		c.118C>T	p.Arg40Cys	missense	Exon 1 of 25	ENSP00000493780.1	A0A2R8YDH4
ENSG00000285130	ENST00000646862.1		c.118C>T	p.Arg40Cys	missense	Exon 1 of 6	ENSP00000494599.1	A0A2R8Y577

Frequencies

GnomAD3 genomes

AF:

0.000401

AC:

AN:

151944

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000780

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000299

AC:

AN:

90414

AF XY:

0.000255

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000108

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000757

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000692

AC:

924

AN:

1335348

Hom.:

Cov.:

AF XY:

0.000668

AC XY:

440

AN XY:

658314

show subpopulations

African (AFR)

AF:

0.0000741

AC:

AN:

26976

American (AMR)

AF:

0.000166

AC:

AN:

30084

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23560

East Asian (EAS)

AF:

0.00

AC:

AN:

30398

South Asian (SAS)

AF:

0.0000134

AC:

AN:

74504

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33070

Middle Eastern (MID)

AF:

0.000253

AC:

AN:

3952

European-Non Finnish (NFE)

AF:

0.000842

AC:

890

AN:

1057314

Other (OTH)

AF:

0.000451

AC:

AN:

55490

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

134

179

224

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.000401

AC:

AN:

151944

Hom.:

Cov.:

AF XY:

0.000431

AC XY:

AN XY:

74206

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41400

American (AMR)

AF:

0.000262

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10564

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000780

AC:

AN:

67942

Other (OTH)

AF:

0.000479

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

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:

0.000325

Hom.:

Bravo

AF:

0.000427

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Friedreich ataxia 1 (1)

Hypertrophic cardiomyopathy (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.039

BayesDel_noAF

Pathogenic

0.18

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.78

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.79

MetaSVM

Uncertain

0.51

MutationAssessor

Benign

1.9

PhyloP100

0.021

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.60

Sift

Uncertain

0.0040

Sift4G

Benign

0.17

Polyphen

0.99

Vest4

0.27

MVP

0.95

ClinPred

0.19

GERP RS

2.3

PromoterAI

0.050

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.12

gMVP

0.30

Mutation Taster

=12/88

disease causing (ClinVar)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over