chr9-69035900-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP3BS1_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).

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:5B:1

Conservation

PhyloP100: 0.0210

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:

ENSG00000285130 (HGNC:):

ENSG00000285130 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.793

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome 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 gnomad4_exome. There are 440 alleles in male gnomad4_exome subpopulation. Median coverage is 36. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FXN	NM_000144.5 link	c.118C>T	p.Arg40Cys	missense_variant	Exon 1 of 5	ENST00000484259.3	NP_000135.2	Q16595-1A0A0S2Z3G4
FXN	NM_181425.3 link	c.118C>T	p.Arg40Cys	missense_variant	Exon 1 of 5		NP_852090.1	Q16595-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FXN	ENST00000484259.3 link	c.118C>T	p.Arg40Cys	missense_variant	Exon 1 of 5	3	NM_000144.5	ENSP00000419243.2		Q16595-1
ENSG00000285130	ENST00000642889.1 link	c.118C>T	p.Arg40Cys	missense_variant	Exon 1 of 25			ENSP00000493780.1		A0A2R8YDH4

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

GnomAD3 exomes

AF:

0.000299

AC:

AN:

90414

Hom.:

AF XY:

0.000255

AC XY:

AN XY:

50990

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 SAS 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

Gnomad4 AFR exome

AF:

0.0000741

Gnomad4 AMR exome

AF:

0.000166

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000134

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000842

Gnomad4 OTH exome

AF:

0.000451

GnomAD4 genome

AF:

0.000401

AC:

AN:

151944

Hom.:

Cov.:

AF XY:

0.000431

AC XY:

AN XY:

74206

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000780

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000325

Hom.:

Bravo

AF:

0.000427

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 26, 2023	Reported in the heterozygous state in an individual with hypertrophic cardiomyopathy, however the individual also harbored a variant in MYBPC3 (PMID: 15936968); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15936968) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 22, 2024	The FXN c.118C>T; p.Arg40Cys variant (rs145854903, ClinVar Variation ID 264451) is reported along with a likely pathogenic MYBPC3 variant in an individual with hypertrophic cardiomyopathy (Van Driest 2005). This variant is found predominantly in the non-Finnish European population with an allele frequency of 0.07% (36/48340 alleles) in the Genome Aggregation Database (v2.1.1). In vitro functional analysis of the variant protein showed defective cleavage leading to poor protein maturation; however, both FXN mRNA and protein levels were unaffected in patient’s cultured fibroblasts (Van Driest 2005). Additionally, expression of FXN mutant protein in yeast devoid of endogenous FXN were phenotypically indistinguishable. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.597). Due to conflicting information, the clinical significance of this variant is uncertain at this time. References: Van Driest SL et al. Molecular and functional characterization of a human frataxin mutation found in hypertrophic cardiomyopathy. Mol Genet Metab. 2005 Aug. PMID: 15936968. -

not specified

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 24, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 16, 2024	Variant summary: FXN c.118C>T (p.Arg40Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 90414 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in FXN causing Friedreich Ataxia (0.0003 vs 0.0011), allowing no conclusion about variant significance. c.118C>T has been reported in the heterozygous state in an individual affected with hypertrophic cardiomyopathy (Van Driest_2005). However, this individual was also found carrying MYBPC3 c.2429G>A (p.Arg810His), which may have contributed to the patient's phenotype. This report does not provide unequivocal conclusions about association of the variant with Friedreich Ataxia. Van Driest_2005 also provided experimental evidence demonstrating that the variant prevented the cleavage of the inactive-precursor form of frataxin to the active-mature form. However, when the investigators examined protein levels in patient fibroblasts, the levels of mature frataxin were similar to those seen in controls, not allowing for convincing conclusions about the variant effect. The following publication has been ascertained in the context of this evaluation (PMID: 15936968). ClinVar contains an entry for this variant (Variation ID: 264451). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2017

The p.R40C variant (also known as c.118C>T), located in coding exon 1 of the FXN gene, results from a C to T substitution at nucleotide position 118. The arginine at codon 40 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant co-occurred with a missense alteration in MYBPC3 in a male patient diagnosed with hypertrophic cardiomyopathy at 12 years of age. The same group performed in vitro studies of the p.R40C variant and showed it was more sensitive to oxidative stress under metabolically demanding conditions; however, a skin biopsy from the patient mentioned above showed normal levels of frataxin mRNA and protein (Van Driest SL, Mol. Genet. Metab. 2005 Aug; 85(4):280-5). This amino acid position is well conserved on limited sequence alignment. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Apr 18, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.039

BayesDel_noAF

Pathogenic

0.18

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

T;.;.;T;.;.

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.78

.;T;T;T;T;T

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.79

D;D;D;D;D;D

MetaSVM

Uncertain

0.51

MutationAssessor

Benign

1.9

L;L;L;L;.;.

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.6

.;N;N;.;.;.

REVEL

Uncertain

0.60

Sift

Uncertain

0.0040

.;D;D;.;.;.

Sift4G

Benign

0.17

.;T;T;.;.;.

Polyphen

0.99

D;D;.;D;.;.

Vest4

0.27, 0.33

MVP

0.95

ClinPred

0.19

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.12

gMVP

0.30

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