rs144610605

Positions:

• chr9-69072677-A-G
• chr9-69072677-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000144.5(FXN):​c.548A>G​(p.His183Arg) variant causes a missense change involving the alteration of a 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: 32)
• 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 8 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, 0.965

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FXN	NM_000144.5	c.548A>G	p.His183Arg	missense_variant	5/5	ENST00000484259.3
FXN	NM_181425.3	c.556A>G	p.Met186Val	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FXN	ENST00000484259.3	c.548A>G	p.His183Arg	missense_variant	5/5	3	NM_000144.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Uncertain	25
DANN	Benign	0.95
DEOGEN2	Pathogenic	0.90	D;D;D;D
Eigen	Benign	0.062
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.74	.;T;.;T
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.70	D
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-7.0	.;.;.;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.014	.;.;.;D
Sift4G	Benign	0.11	.;.;.;T
Polyphen		1.0	D;D;.;.
Vest4		0.91
MutPred		0.76		Loss of catalytic residue at L185 (P = 0.1395);Loss of catalytic residue at L185 (P = 0.1395);.;.;
MVP		0.95
MPC		1.1
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.94
gMVP		0.76

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; COSMIC: COSV66010508;