rs143232208

chr9-69035789-ACT-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000144.5(FXN):c.11_12del(p.Leu4ArgfsTer88) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000443 in 1,355,844 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: FXN NM_000144.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.22

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 22 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-69035789-ACT-A is Pathogenic according to our data. Variant chr9-69035789-ACT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 263606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FXN	NM_000144.5	c.11_12del	p.Leu4ArgfsTer88	frameshift_variant	1/5	ENST00000484259.3
FXN	NM_181425.3	c.11_12del	p.Leu4ArgfsTer88	frameshift_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FXN	ENST00000484259.3	c.11_12del	p.Leu4ArgfsTer88	frameshift_variant	1/5	3	NM_000144.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000443 AC: 6 AN: 1355844 Hom.: 0 AF XY: 0.00000748 AC XY: 5 AN XY: 668598

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000302

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000187

Gnomad4 OTH exome AF: 0.0000530

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 24, 2015

The c.11_12delTC variant, located in coding exon 1 of the FXN gene, results from a deletion of two nucleotides between nucleotide positions 11 and 12, causing a translational frameshift with a predicted alternate stop codon (p.L4Rfs*88). This variant was observed in two Malaysian siblings, both exhibiting features of Friedreich ataxia including nonobstructive hypertrophic cardiomyopathy. These siblings were compound heterozygotes, carrying this alteration and a repeat expansion mutation on the opposite allele. This variant was inherited from their mother, and both parents were clinically unaffected (Spacey SD, Can J Neurol Sci 2004 Aug; 31(3):383-6). This variant was also reported in another cohort of patients with Friedreich ataxia (Lazaropoulos M. Ann Clin Transl Neurol. 2015 Aug;2(8):831-42). This variant was previously reported in the SNPDatabase as rs143232208. This variant was not reported in population-based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. While truncating alterations in FXN are not a common cause of Friedreich ataxia and their functional consequences have not been well described, frameshifts are typically deleterious in nature (ACMG Standards and guidelines for the interpretation of sequence variants. Genet Med. 2015;17(5):405-24). Based on the majority of available evidence to date, this variant is likely to be pathogenic when in trans with another FXN mutation; however, expression and severity cannot be predicted. -

Friedreich ataxia 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genomic Medicine Lab, University of California San Francisco

May 01, 2023

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 23, 2023

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26339677, 28789479, 15376485) -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs143232208; hg19: chr9-71650705;