9-69037284-AAAGAAGAAGAAGAAG-AAAGAAGAAGAAGAAGAAG

Variant names:

• chr9-69037284-A-AAAG
• rs193922938
• NM_000144.5:c.165+1355_165+1357dupGAA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_000144.5(FXN):​c.165+1355_165+1357dupGAA variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0018 (1 hom., cov: 0)
• Consequence: FXN NM_000144.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.327
• Publications: 0 publications found

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

ENSG00000285130 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00183 (143/78056) while in subpopulation EAS AF = 0.0183 (59/3222). AF 95% confidence interval is 0.0146. There are 1 homozygotes in GnomAd4. There are 80 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FXN	NM_000144.5	c.165+1355_165+1357dupGAA		intron_variant	Intron 1 of 4	ENST00000484259.3	NP_000135.2
FXN	NM_181425.3	c.165+1355_165+1357dupGAA		intron_variant	Intron 1 of 4		NP_852090.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FXN	ENST00000484259.3	c.165+1337_165+1338insAAG		intron_variant	Intron 1 of 4	3	NM_000144.5	ENSP00000419243.2
ENSG00000285130	ENST00000642889.1	c.165+1337_165+1338insAAG		intron_variant	Intron 1 of 24			ENSP00000493780.1

Frequencies

GnomAD3 genomes AF: 0.00183 AC: 143 AN: 78064 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00161

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000885

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0183

Gnomad SAS AF: 0.0112

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0125

Gnomad NFE AF: 0.000380

Gnomad OTH AF: 0.00207

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

GnomAD4 genome AF: 0.00183 AC: 143 AN: 78056 Hom.: 1 Cov.: 0 AF XY: 0.00229 AC XY: 80 AN XY: 34950

African (AFR) AF: 0.00156 AC: 33 AN: 21158

American (AMR) AF: 0.000883 AC: 6 AN: 6794

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2180

East Asian (EAS) AF: 0.0183 AC: 59 AN: 3222

South Asian (SAS) AF: 0.0113 AC: 25 AN: 2218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1330

Middle Eastern (MID) AF: 0.0141 AC: 2 AN: 142

European-Non Finnish (NFE) AF: 0.000405 AC: 16 AN: 39500

Other (OTH) AF: 0.00208 AC: 2 AN: 962

Alfa AF: 0.00 Hom.: 0

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

Other links and lift over

dbSNP: rs193922938; hg19: chr9-71652200;