rs142133355

Variant names:

• chr9-69035784-T-A
• rs142133355
• NM_000144.5:c.2T>A

Your query was ambiguous. Multiple possible variants found:

• chr9-69035784-T-A
• chr9-69035784-T-C
• chr9-69035784-T-G

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.2T>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000397 in 1,510,212 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: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: FXN NM_000144.5 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.25
• Publications: 1 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.2T>A	p.Met1?	start_lost	Exon 1 of 5	NP_000135.2
	FXN	NM_181425.3		c.2T>A	p.Met1?	start_lost	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.2T>A	p.Met1?	start_lost	Exon 1 of 5	ENSP00000419243.2
	ENSG00000285130	ENST00000642889.1		c.2T>A	p.Met1?	start_lost	Exon 1 of 25	ENSP00000493780.1
	ENSG00000285130	ENST00000646862.1		c.2T>A	p.Met1?	start_lost	Exon 1 of 6	ENSP00000494599.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152070 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000368 AC: 5 AN: 1358028 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 669648

African (AFR) AF: 0.00 AC: 0 AN: 28622

American (AMR) AF: 0.00 AC: 0 AN: 33784

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24352

East Asian (EAS) AF: 0.0000300 AC: 1 AN: 33360

South Asian (SAS) AF: 0.00 AC: 0 AN: 76384

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32934

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4010

European-Non Finnish (NFE) AF: 0.00000375 AC: 4 AN: 1067862

Other (OTH) AF: 0.00 AC: 0 AN: 56720

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74410

African (AFR) AF: 0.00 AC: 0 AN: 41562

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67966

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.045
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Pathogenic	0.82	D
PhyloP100		2.3
PROVEAN	Benign	-1.8	N
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.97	D
Vest4		0.86
MutPred		0.56		Loss of stability (P = 0.0184)
MVP		0.90
ClinPred		0.99	D
GERP RS		1.6
PromoterAI		0.10	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.87
gMVP		0.54
Mutation Taster		=0/200	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: rs142133355; hg19: chr9-71650700;