rs141935559

Variant names:

• chr9-69035935-GC-G
• rs141935559
• NM_000144.5:c.157delC

Your query was ambiguous. Multiple possible variants found:

• chr9-69035935-GC-G
• chr9-69035935-GC-GCC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000144.5(FXN):​c.157delC​(p.Arg53AlafsTer23) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000764 in 1,309,544 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: FXN NM_000144.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: -0.923
• 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: Labcorp Genetics (formerly Invitae), G2P
• Friedreich ataxia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285130 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-69035935-GC-G is Pathogenic according to our data. Variant chr9-69035935-GC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 3985.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000144.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FXN	NM_000144.5	MANE Select	c.157delC	p.Arg53AlafsTer23	frameshift	Exon 1 of 5	NP_000135.2
	FXN	NM_181425.3		c.157delC	p.Arg53AlafsTer23	frameshift	Exon 1 of 5	NP_852090.1	Q16595-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FXN	ENST00000484259.3	TSL:3 MANE Select	c.157delC	p.Arg53AlafsTer23	frameshift	Exon 1 of 5	ENSP00000419243.2	Q16595-1
	ENSG00000285130	ENST00000642889.1		c.157delC	p.Arg53AlafsTer14	frameshift	Exon 1 of 25	ENSP00000493780.1	A0A2R8YDH4
	ENSG00000285130	ENST00000646862.1		c.157delC	p.Arg53AlafsTer23	frameshift	Exon 1 of 6	ENSP00000494599.1	A0A2R8Y577

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 79032 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.64e-7 AC: 1 AN: 1309544 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 645846

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26248

American (AMR) AF: 0.00 AC: 0 AN: 26822

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22638

East Asian (EAS) AF: 0.00 AC: 0 AN: 28126

South Asian (SAS) AF: 0.00 AC: 0 AN: 72944

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31806

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3850

European-Non Finnish (NFE) AF: 9.59e-7 AC: 1 AN: 1043294

Other (OTH) AF: 0.00 AC: 0 AN: 53816

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Friedreich ataxia (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.92
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs141935559; hg19: chr9-71650851;