rs147643987

Positions:

• chr9-69035783-A-C
• chr9-69035783-A-G
• chr9-69035783-A-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate PM2

The NM_000144.5(FXN):​c.1A>C​(p.Met1?) variant causes a start lost 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 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.62

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 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_000144.5 (FXN) was described as [Pathogenic] in ClinVar as 3983
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FXN	NM_000144.5	c.1A>C	p.Met1?	start_lost	1/5	ENST00000484259.3
FXN	NM_181425.3	c.1A>C	p.Met1?	start_lost	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FXN	ENST00000484259.3	c.1A>C	p.Met1?	start_lost	1/5	3	NM_000144.5	P1

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
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A;A
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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.97
gMVP		0.29

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: rs147643987; hg19: chr9-71650699;