chr9-69072646-T-G

Position:

• chr9-69072646-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000144.5(FXN):​c.517T>G​(p.Trp173Gly) 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. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FXN NM_000144.5 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.41

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a mutagenesis_site Loss of 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 9-69072646-T-G is Pathogenic according to our data. Variant chr9-69072646-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3984.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FXN	NM_000144.5	c.517T>G	p.Trp173Gly	missense_variant	5/5	ENST00000484259.3	NP_000135.2
FXN	NM_181425.3	c.525T>G	p.Thr175Thr	synonymous_variant	5/5		NP_852090.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FXN	ENST00000484259.3	c.517T>G	p.Trp173Gly	missense_variant	5/5	3	NM_000144.5	ENSP00000419243.2
ENSG00000285130	ENST00000642889.1	c.166-27255T>G		intron_variant				ENSP00000493780.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Friedreich ataxia Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

OMIM

Dec 30, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.98	D;D;D;D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.65	.;T;.;T
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.95	D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-11	.;.;.;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0030	.;.;.;D
Sift4G	Uncertain	0.0040	.;.;.;D
Polyphen		1.0	D;D;.;.
Vest4		0.97
MutPred		0.92		Gain of disorder (P = 0.0106);Gain of disorder (P = 0.0106);.;.;
MVP		0.95
MPC		1.1
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.98
gMVP		0.94

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: rs56214919; hg19: chr9-71687562;