chr9-69035783-A-T

Variant names:

• chr9-69035783-A-T
• rs147643987
• NM_000144.5:c.1A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PS1_Moderate PM2

The NM_000144.5(FXN):​c.1A>T​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000737 in 1,356,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: FXN NM_000144.5 initiator_codon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.62
• Publications: 8 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_pathogenic. The variant received 8 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 5 pathogenic variants. Next in-frame start position is after 76 codons. Genomic position: 69046445. Lost 0.357 part of the original CDS.
• PS1: Another start lost variant in NM_000144.5 (FXN) was described as [Pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FXN	NM_000144.5	MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 5	NP_000135.2
	FXN	NM_181425.3		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 5	NP_852090.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FXN	ENST00000484259.3	TSL:3 MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 5	ENSP00000419243.2
	ENSG00000285130	ENST00000642889.1		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 25	ENSP00000493780.1
	ENSG00000285130	ENST00000646862.1		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 6	ENSP00000494599.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000920 AC: 1 AN: 108670 AF XY: 0.0000166

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: 7.37e-7 AC: 1 AN: 1356038 Hom.: 0 Cov.: 29 AF XY: 0.00000150 AC XY: 1 AN XY: 668624

⚠️ 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: 28502

American (AMR) AF: 0.00 AC: 0 AN: 33570

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24314

East Asian (EAS) AF: 0.00 AC: 0 AN: 33144

South Asian (SAS) AF: 0.0000131 AC: 1 AN: 76136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32828

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4004

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1066924

Other (OTH) AF: 0.00 AC: 0 AN: 56616

⚠️ 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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.50
CADD	Uncertain	23
DANN	Benign	0.94
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.087
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Pathogenic	0.87	D
PhyloP100		2.6
PROVEAN	Benign	-1.1	N
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.70	P
Vest4		0.85
MutPred		0.56		Loss of catalytic residue at M1 (P = 0.0394)
MVP		0.99
ClinPred		0.99	D
GERP RS		2.8
PromoterAI		0.016	Neutral
Varity_R		0.97
gMVP		0.29
Mutation Taster		=1/199	disease causing

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: rs147643987; hg19: chr9-71650699;