rs141858334

Positions:

chr9-69046398-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1PM2BP4_StrongBP6BS1

The NM_000144.5(FXN):c.179G>A(p.Arg60His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000923 in 1,613,962 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000075 ( 1 hom. )

Consequence

FXN
NM_000144.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -0.155

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 Likely_benign. Variant got -5 ACMG points.

PM1

In a chain Frataxin(56-210) (size 154) in uniprot entity FRDA_HUMAN there are 8 pathogenic changes around while only 2 benign (80%) in NM_000144.5

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0048853755).

BP6

Variant 9-69046398-G-A is Benign according to our data. Variant chr9-69046398-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211055.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000256 (39/152246) while in subpopulation EAS AF= 0.00385 (20/5190). AF 95% confidence interval is 0.00255. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FXN	NM_000144.5 linkuse as main transcript	c.179G>A	p.Arg60His	missense_variant	2/5	ENST00000484259.3	NP_000135.2
FXN	NM_181425.3 linkuse as main transcript	c.179G>A	p.Arg60His	missense_variant	2/5		NP_852090.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FXN	ENST00000484259.3 linkuse as main transcript	c.179G>A	p.Arg60His	missense_variant	2/5	3	NM_000144.5	ENSP00000419243	P1	Q16595-1

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000435

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00384

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000334

AC:

AN:

251406

Hom.:

AF XY:

0.000309

AC XY:

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00402

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000753

AC:

110

AN:

1461716

Hom.:

Cov.:

AF XY:

0.0000688

AC XY:

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00214

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000256

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00385

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000124

Hom.:

Bravo

AF:

0.000223

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000305

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 31, 2015

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 20, 2019

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 20, 2013

This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.38

CADD

Benign

0.34

DANN

Benign

0.54

DEOGEN2

Benign

0.33

T;.;.;T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0032

LIST_S2

Benign

0.39

.;T;T;T;T

M_CAP

Benign

0.027

MetaRNN

Benign

0.0049

T;T;T;T;T

MetaSVM

Benign

-0.34

MutationAssessor

Benign

0.035

N;N;N;N;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.21

PROVEAN

Benign

0.27

.;N;N;.;.

REVEL

Benign

0.21

Sift

Benign

0.53

.;T;T;.;.

Sift4G

Benign

0.58

.;T;T;.;.

Polyphen

0.0020

B;B;.;B;.

Vest4

0.086, 0.047

MVP

0.56

ClinPred

0.0018

GERP RS

-1.9

Varity_R

0.040

gMVP

0.19

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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