Genetic Variant FXN:c.165+1346_165+1357dupGAAGAAGAAGAA (chr9-69037284-A-AAAGAAGAAGAAG) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_000144.5(FXN):c.165+1346_165+1357dupGAAGAAGAAGAA variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0015 ( 3 hom., cov: 0)

Consequence

FXN
NM_000144.5 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.327

Publications

0 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: Benign. The variant received -10 ACMG points.

BP6

Variant 9-69037284-A-AAAGAAGAAGAAG is Benign according to our data. Variant chr9-69037284-A-AAAGAAGAAGAAG is described in ClinVar as Likely_benign. ClinVar VariationId is 4084955.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00147 (115/78054) while in subpopulation SAS AF = 0.00857 (19/2216). AF 95% confidence interval is 0.00561. There are 3 homozygotes in GnomAd4. There are 61 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FXN	NM_000144.5 link	c.165+1346_165+1357dupGAAGAAGAAGAA		intron_variant	Intron 1 of 4	ENST00000484259.3	NP_000135.2	Q16595-1A0A0S2Z3G4
FXN	NM_181425.3 link	c.165+1346_165+1357dupGAAGAAGAAGAA		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+1337_165+1338insAAGAAGAAGAAG		intron_variant	Intron 1 of 4	3	NM_000144.5	ENSP00000419243.2		Q16595-1
ENSG00000285130	ENST00000642889.1 link	c.165+1337_165+1338insAAGAAGAAGAAG		intron_variant	Intron 1 of 24			ENSP00000493780.1		A0A2R8YDH4

Frequencies

GnomAD3 genomes

AF:

0.00147

AC:

115

AN:

78062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000710

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00487

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00248

Gnomad SAS

AF:

0.00850

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00625

Gnomad NFE

AF:

0.000886

Gnomad OTH

AF:

0.00415

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.00147

AC:

115

AN:

78054

Hom.:

Cov.:

AF XY:

0.00175

AC XY:

AN XY:

34948

show subpopulations

African (AFR)

AF:

0.000709

AC:

AN:

21158

American (AMR)

AF:

0.00486

AC:

AN:

6794

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2180

East Asian (EAS)

AF:

0.00248

AC:

AN:

3222

South Asian (SAS)

AF:

0.00857

AC:

AN:

2216

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1330

Middle Eastern (MID)

AF:

0.00704

AC:

AN:

142

European-Non Finnish (NFE)

AF:

0.000886

AC:

AN:

39500

Other (OTH)

AF:

0.00416

AC:

AN:

962

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.33

Splicing

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

Publications

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9-69037284-AAAGAAGAAGAAGAAG-AAAGAAGAAGAAGAAGAAGAAGAAGAAG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over