Variant chr9-69053240-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS1_ModeratePM1PM2PP3_Moderate

The NM_000144.5(FXN):c.364G>T(p.Asp122Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FXN
NM_000144.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.11

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PS1

Transcript NM_000144.5 (FXN) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM1

In a mutagenesis_site Does not affect interaction with the core iron-sulfur cluster assembly complex. Does not affect mitochondrial localization. Does not affect proteolytic processing. (size 0) in uniprot entity FRDA_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.935

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FXN	NM_000144.5 linkuse as main transcript	c.364G>T	p.Asp122Tyr	missense_variant	3/5	ENST00000484259.3	NP_000135.2
FXN	NM_181425.3 linkuse as main transcript	c.364G>T	p.Asp122Tyr	missense_variant	3/5		NP_852090.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FXN	ENST00000484259.3 linkuse as main transcript	c.364G>T	p.Asp122Tyr	missense_variant	3/5	3	NM_000144.5	ENSP00000419243	P1	Q16595-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461626

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727116

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

D;.;.;D;D;D;.

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

.;D;D;D;.;D;D

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.94

D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

3.3

M;M;M;M;.;.;.

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-6.9

.;D;D;.;N;D;.

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0030

.;D;D;.;T;D;.

Sift4G

Uncertain

0.0080

.;D;D;.;.;D;.

Polyphen

1.0

D;D;.;D;.;.;.

Vest4

0.83, 0.76, 0.93

MutPred

0.82

Gain of phosphorylation at D122 (P = 0.0371);Gain of phosphorylation at D122 (P = 0.0371);Gain of phosphorylation at D122 (P = 0.0371);Gain of phosphorylation at D122 (P = 0.0371);.;.;Gain of phosphorylation at D122 (P = 0.0371);

MVP

0.96

MPC

1.1

ClinPred

1.0

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over