FXN p.Met76Leu

Variant names:

• chr9-69046445-A-T
• NM_000144.5:c.226A>T
• FXN p.Met76Leu

Your query was ambiguous. Multiple possible variants found:

• chr9-69046445-A-T
• chr9-69046445-A-C
• chr9-69046445-ATG-TTA
• chr9-69046445-ATG-CTT
• chr9-69046445-ATG-CTC
• chr9-69046445-ATG-CTA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000144.5(FXN):​c.226A>T​(p.Met76Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign 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. M76V) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FXN NM_000144.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.704
• Publications: 0 publications found

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]

FXN Gene-Disease associations (from GenCC):

• Friedreich ataxia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Friedreich ataxia 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Friedreich ataxia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285130 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20817855).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000144.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FXN	NM_000144.5	MANE Select	c.226A>T	p.Met76Leu	missense	Exon 2 of 5	NP_000135.2
	FXN	NM_181425.3		c.226A>T	p.Met76Leu	missense	Exon 2 of 5	NP_852090.1	Q16595-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FXN	ENST00000484259.3	TSL:3 MANE Select	c.226A>T	p.Met76Leu	missense	Exon 2 of 5	ENSP00000419243.2	Q16595-1
	FXN	ENST00000377270.8	TSL:1	c.1A>T	p.Met1?	initiator_codon	Exon 3 of 6	ENSP00000366482.4	C9JAX1
	FXN	ENST00000498653.5	TSL:1	c.1A>T	p.Met1?	initiator_codon	Exon 2 of 5	ENSP00000418015.1	C9JAX1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	0.0017	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	14
DANN	Benign	0.59
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.70
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.16
Sift	Benign	0.45	T
Sift4G	Benign	0.82	T
Varity_R		0.14
gMVP		0.31
Mutation Taster		=117/83	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr9-71661361;