9-69035952-G-C

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_000144.5(FXN):c.165+5G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,309,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

FXN
NM_000144.5 splice_region, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.30

Publications

4 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: G2P, Labcorp Genetics (formerly Invitae)
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: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 9-69035952-G-C is Pathogenic according to our data. Variant chr9-69035952-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 3571552.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FXN	NM_000144.5 link	c.165+5G>C		splice_region_variant, intron_variant	Intron 1 of 4	ENST00000484259.3	NP_000135.2	Q16595-1A0A0S2Z3G4
FXN	NM_181425.3 link	c.165+5G>C		splice_region_variant, intron_variant	Intron 1 of 4		NP_852090.1	Q16595-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FXN	ENST00000484259.3 link	c.165+5G>C		splice_region_variant, intron_variant	Intron 1 of 4	3	NM_000144.5	ENSP00000419243.2		Q16595-1
ENSG00000285130	ENST00000642889.1 link	c.165+5G>C		splice_region_variant, intron_variant	Intron 1 of 24			ENSP00000493780.1		A0A2R8YDH4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1309552

Hom.:

Cov.:

AF XY:

0.0000108

AC XY:

AN XY:

645530

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26402

American (AMR)

AF:

0.00

AC:

AN:

26102

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22766

East Asian (EAS)

AF:

0.000107

AC:

AN:

28022

South Asian (SAS)

AF:

0.00

AC:

AN:

72308

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32660

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3858

European-Non Finnish (NFE)

AF:

0.0000125

AC:

AN:

1043450

Other (OTH)

AF:

0.0000370

AC:

AN:

53984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Feb 16, 2024

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has been reported in multiple individuals with a single recessive pathogenic variant in the same gene, which is suggestive of pathogenicity. Evidence from patient-derived sample(s) with this variant suggests the encoded protein has abnormal function, however, these results may be due to other factors. This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) Computational tools yielded predictions that this variant may interfere with normal RNA splicing. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.78

PhyloP100

1.3

PromoterAI

-0.96

Under-expression

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=2/98

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

0.95

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.95

Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over