9-69035858-C-G

Variant names:

• chr9-69035858-C-G
• rs536676174
• NM_000144.5:c.76C>G

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.76C>G​(p.Arg26Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000743 in 1,345,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. R26W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: FXN NM_000144.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.518
• 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=0.07274678).

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.76C>G	p.Arg26Gly	missense	Exon 1 of 5	NP_000135.2
	FXN	NM_181425.3		c.76C>G	p.Arg26Gly	missense	Exon 1 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.76C>G	p.Arg26Gly	missense	Exon 1 of 5	ENSP00000419243.2	Q16595-1
	ENSG00000285130	ENST00000642889.1		c.76C>G	p.Arg26Gly	missense	Exon 1 of 25	ENSP00000493780.1	A0A2R8YDH4
	ENSG00000285130	ENST00000646862.1		c.76C>G	p.Arg26Gly	missense	Exon 1 of 6	ENSP00000494599.1	A0A2R8Y577

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.43e-7 AC: 1 AN: 1345770 Hom.: 0 Cov.: 36 AF XY: 0.00000151 AC XY: 1 AN XY: 663354

African (AFR) AF: 0.00 AC: 0 AN: 27366

American (AMR) AF: 0.00 AC: 0 AN: 31806

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23892

East Asian (EAS) AF: 0.00 AC: 0 AN: 31604

South Asian (SAS) AF: 0.0000133 AC: 1 AN: 75350

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4010

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1062490

Other (OTH) AF: 0.00 AC: 0 AN: 56072

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	9.5
DANN	Benign	0.67
DEOGEN2	Benign	0.33	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0069	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	0.46	N
PhyloP100		0.52
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.16
Sift	Benign	0.42	T
Sift4G	Benign	0.34	T
Polyphen		0.0	B
Vest4		0.055
MutPred		0.20		Loss of methylation at R26 (P = 0.0182)
MVP		0.34
ClinPred		0.032	T
GERP RS		-2.1
PromoterAI		-0.056	Neutral
Varity_R		0.066
gMVP		0.29
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs536676174; hg19: chr9-71650774;