9-69035894-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_000144.5(FXN):c.112G>A(p.Gly38Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000289 in 1,487,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

FXN
NM_000144.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.71

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 -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.047568798).

BP6

Variant 9-69035894-G-A is Benign according to our data. Variant chr9-69035894-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2515732.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FXN	NM_000144.5 linkuse as main transcript	c.112G>A	p.Gly38Ser	missense_variant	1/5	ENST00000484259.3
FXN	NM_181425.3 linkuse as main transcript	c.112G>A	p.Gly38Ser	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FXN	ENST00000484259.3 linkuse as main transcript	c.112G>A	p.Gly38Ser	missense_variant	1/5	3	NM_000144.5	P1	Q16595-1

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

151824

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000532

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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

GnomAD4 exome

AF:

0.0000150

AC:

AN:

1335852

Hom.:

Cov.:

AF XY:

0.0000121

AC XY:

AN XY:

658496

show subpopulations

Gnomad4 AFR exome

AF:

0.000593

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000720

GnomAD4 genome

AF:

0.000151

AC:

AN:

151932

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.000530

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000227

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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

0.084

BayesDel_addAF

Benign

-0.074

BayesDel_noAF

Benign

-0.34

Cadd

Benign

0.41

Dann

Benign

0.79

DEOGEN2

Benign

0.32

T;.;.;T;.;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.035

M_CAP

Pathogenic

0.75

MetaRNN

Benign

0.048

T;T;T;T;T;T

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

0.85

L;L;L;L;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.51

Polyphen

0.0030

B;B;.;B;.;.

Vest4

0.053, 0.12

MutPred

0.44

Gain of glycosylation at G38 (P = 0.0152);Gain of glycosylation at G38 (P = 0.0152);Gain of glycosylation at G38 (P = 0.0152);Gain of glycosylation at G38 (P = 0.0152);Gain of glycosylation at G38 (P = 0.0152);Gain of glycosylation at G38 (P = 0.0152);

MVP

0.50

ClinPred

0.095

GERP RS

-0.71

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.0

Varity_R

0.047

gMVP

0.20

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