NM_000144.5:c.70C>T

Variant names:

• chr9-69035852-C-T
• rs1052328470
• NM_000144.5:c.70C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000144.5(FXN):​c.70C>T​(p.Leu24Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,500,612 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. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: FXN NM_000144.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -1.20
• 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: Labcorp Genetics (formerly Invitae), G2P
• Friedreich ataxia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285130 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08719745).

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.70C>T	p.Leu24Phe	missense	Exon 1 of 5	NP_000135.2
	FXN	NM_181425.3		c.70C>T	p.Leu24Phe	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.70C>T	p.Leu24Phe	missense	Exon 1 of 5	ENSP00000419243.2	Q16595-1
	ENSG00000285130	ENST00000642889.1		c.70C>T	p.Leu24Phe	missense	Exon 1 of 25	ENSP00000493780.1	A0A2R8YDH4
	ENSG00000285130	ENST00000646862.1		c.70C>T	p.Leu24Phe	missense	Exon 1 of 6	ENSP00000494599.1	A0A2R8Y577

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152078 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000200 AC: 2 AN: 99898 AF XY: 0.0000179

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000540

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000119 AC: 160 AN: 1348534 Hom.: 0 Cov.: 36 AF XY: 0.000111 AC XY: 74 AN XY: 664800

African (AFR) AF: 0.0000363 AC: 1 AN: 27520

American (AMR) AF: 0.00 AC: 0 AN: 32220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23996

East Asian (EAS) AF: 0.00 AC: 0 AN: 31906

South Asian (SAS) AF: 0.00 AC: 0 AN: 75650

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4002

European-Non Finnish (NFE) AF: 0.000149 AC: 158 AN: 1063842

Other (OTH) AF: 0.0000178 AC: 1 AN: 56210

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152078 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74294

African (AFR) AF: 0.000121 AC: 5 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000718

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	0.65
DANN	Benign	0.90
DEOGEN2	Benign	0.31	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.087	T
MetaSVM	Uncertain	-0.075	T
MutationAssessor	Benign	0.55	N
PhyloP100		-1.2
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.12
Sift	Benign	0.31	T
Sift4G	Benign	0.55	T
Polyphen		0.0010	B
Vest4		0.067
MVP		0.44
ClinPred		0.035	T
GERP RS		-2.4
PromoterAI		0.18	Neutral
Varity_R		0.053
gMVP		0.097
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: rs1052328470; hg19: chr9-71650768;