chr9-69064942-G-C

Variant names:

• chr9-69064942-G-C
• rs104894107
• NM_000144.5:c.389G>C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000144.5(FXN):​c.389G>C​(p.Gly130Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000241 in 1,454,046 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. G130V) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: FXN NM_000144.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.30

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]

ENSG00000285130 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a mutagenesis_site Does not affect interaction with the core iron-sulfur cluster assembly complex. Does not affect mitochondrial localization. Does not affect proteolytic processing. (size 0) in uniprot entity FRDA_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-69064942-G-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FXN	NM_000144.5	c.389G>C	p.Gly130Ala	missense_variant	Exon 4 of 5	ENST00000484259.3	NP_000135.2
FXN	NM_181425.3	c.389G>C	p.Gly130Ala	missense_variant	Exon 4 of 5		NP_852090.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FXN	ENST00000484259.3	c.389G>C	p.Gly130Ala	missense_variant	Exon 4 of 5	3	NM_000144.5	ENSP00000419243.2
ENSG00000285130	ENST00000642889.1	c.165+28995G>C		intron_variant	Intron 1 of 24			ENSP00000493780.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251458 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135904

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 SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000241 AC: 35 AN: 1454046 Hom.: 0 Cov.: 29 AF XY: 0.0000359 AC XY: 26 AN XY: 723994

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: 0.000372

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000272

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000330 AC: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.;.;D;D;D
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D;D;D;.;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Pathogenic	3.9	H;H;H;H;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.5	.;D;D;.;.;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0020	.;D;D;.;.;D
Sift4G	Uncertain	0.0060	.;D;D;.;.;D
Polyphen		1.0	D;D;.;D;.;.
Vest4		0.97, 0.92, 0.96
MutPred		0.89		Loss of glycosylation at S129 (P = 0.0391);Loss of glycosylation at S129 (P = 0.0391);Loss of glycosylation at S129 (P = 0.0391);Loss of glycosylation at S129 (P = 0.0391);.;.;
MVP		0.97
MPC		1.0
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.96
gMVP		0.82

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: rs104894107; hg19: chr9-71679858;