NM_000144.5:c.438C>G

Variant names:

• chr9-69064991-C-G
• rs146818694
• NM_000144.5:c.438C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000144.5(FXN):​c.438C>G​(p.Asn146Lys) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FXN NM_000144.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.86
• Publications: 18 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_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969
• PP5: Variant 9-69064991-C-G is Pathogenic according to our data. Variant chr9-69064991-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 549677.Status of the report is no_assertion_criteria_provided, 0 stars.

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.438C>G	p.Asn146Lys	missense	Exon 4 of 5	NP_000135.2
	FXN	NM_181425.3		c.438C>G	p.Asn146Lys	missense	Exon 4 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.438C>G	p.Asn146Lys	missense	Exon 4 of 5	ENSP00000419243.2	Q16595-1
	FXN	ENST00000377270.8	TSL:1	c.213C>G	p.Asn71Lys	missense	Exon 5 of 6	ENSP00000366482.4	C9JAX1
	FXN	ENST00000498653.5	TSL:1	c.213C>G	p.Asn71Lys	missense	Exon 4 of 5	ENSP00000418015.1	C9JAX1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Friedreich ataxia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		1.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.90		Gain of methylation at N146 (P = 0.01)
MVP		0.95
MPC		1.1
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.92
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs146818694; hg19: chr9-71679907;