rs139616452

Positions:

• chr9-69072673-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1_Moderate PM1 PM2 PP3_Strong

The NM_000144.5(FXN):​c.544C>T​(p.Leu182Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,894 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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FXN NM_000144.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.33

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 10 ACMG points.

• PS1: Transcript NM_000144.5 (FXN) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a chain Extramitochondrial frataxin (size 129) in uniprot entity FRDA_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_000144.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FXN	NM_000144.5	c.544C>T	p.Leu182Phe	missense_variant	5/5	ENST00000484259.3	NP_000135.2
FXN	NM_181425.3	c.552C>T	p.Pro184=	synonymous_variant	5/5		NP_852090.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FXN	ENST00000484259.3	c.544C>T	p.Leu182Phe	missense_variant	5/5	3	NM_000144.5	ENSP00000419243	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461894 Hom.: 0 Cov.: 37 AF XY: 0.00000275 AC XY: 2 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;D;D;D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	.;D;.;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.28	D
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.5	.;.;.;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0030	.;.;.;D
Sift4G	Uncertain	0.0050	.;.;.;D
Polyphen		1.0	D;D;.;.
Vest4		0.96
MutPred		0.91		Gain of catalytic residue at L182 (P = 0.2653);Gain of catalytic residue at L182 (P = 0.2653);.;.;
MVP		0.92
MPC		1.0
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.96
gMVP		0.77

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: rs139616452; hg19: chr9-71687589;