rs147643987

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr9-69035783-A-C
• chr9-69035783-A-G
• chr9-69035783-A-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>C​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FXN	NM_000144.5	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 5	ENST00000484259.3	NP_000135.2
FXN	NM_181425.3	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 5		NP_852090.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FXN	ENST00000484259.3	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 5	3	NM_000144.5	ENSP00000419243.2
ENSG00000285130	ENST00000642889.1	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 25			ENSP00000493780.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Uncertain	23
DANN	Benign	0.94
DEOGEN2	Benign	0.37	T;.;.;T;.;.
Eigen	Benign	-0.087
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	.;D;D;D;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
PhyloP100		2.6
PROVEAN	Benign	-1.1	.;N;N;.;.;.
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	.;D;D;.;.;.
Sift4G	Pathogenic	0.0	.;D;D;.;.;.
Polyphen		0.70	P;P;.;P;.;.
Vest4		0.85, 0.92
MutPred		0.56		Loss of catalytic residue at M1 (P = 0.0394);Loss of catalytic residue at M1 (P = 0.0394);Loss of catalytic residue at M1 (P = 0.0394);Loss of catalytic residue at M1 (P = 0.0394);Loss of catalytic residue at M1 (P = 0.0394);Loss of catalytic residue at M1 (P = 0.0394);
MVP		0.99
ClinPred		0.99	D
GERP RS		2.8
PromoterAI		0.0046	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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;