9-69072677-A-T

Position:

• chr9-69072677-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000144.5(FXN):​c.548A>T​(p.His183Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 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: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FXN NM_000144.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.60

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a chain Frataxin mature form (size 129) in uniprot entity FRDA_HUMAN there are 16 pathogenic changes around while only 2 benign (89%) in NM_000144.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FXN	NM_000144.5	c.548A>T	p.His183Leu	missense_variant	5/5	ENST00000484259.3
FXN	NM_181425.3	c.556A>T	p.Met186Leu	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FXN	ENST00000484259.3	c.548A>T	p.His183Leu	missense_variant	5/5	3	NM_000144.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 727244

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	26
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.89	D;D;D;D
Eigen	Benign	0.038
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;D;.;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.88	D;D;D;D
MetaSVM	Uncertain	0.35	D
MutationTaster	Benign	1.0	D;D;D;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-10	.;.;.;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	.;.;.;D
Sift4G	Benign	0.093	.;.;.;T
Polyphen		1.0	D;D;.;.
Vest4		0.82
MutPred		0.56		Loss of catalytic residue at H183 (P = 0.1357);Loss of catalytic residue at H183 (P = 0.1357);.;.;
MVP		0.92
MPC		1.1
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.96
gMVP		0.75

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: rs144610605; hg19: chr9-71687593;