9-69035907-T-G

Position:

• chr9-69035907-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000144.5(FXN):​c.125T>G​(p.Leu42Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000151 in 1,328,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: FXN NM_000144.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.171

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37623385).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FXN	NM_000144.5	c.125T>G	p.Leu42Arg	missense_variant	1/5	ENST00000484259.3
FXN	NM_181425.3	c.125T>G	p.Leu42Arg	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FXN	ENST00000484259.3	c.125T>G	p.Leu42Arg	missense_variant	1/5	3	NM_000144.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000151 AC: 2 AN: 1328170 Hom.: 0 Cov.: 35 AF XY: 0.00000153 AC XY: 1 AN XY: 654930

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000190

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 12, 2023

Available data are insufficient to determine the clinical significance of the variant at this time. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Computational tools disagree on the variant's effect on normal protein function. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D;.;.;D;.;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.10	N
M_CAP	Pathogenic	0.83	D
MetaRNN	Benign	0.38	T;T;T;T;T;T
MetaSVM	Uncertain	0.39	D
MutationAssessor	Benign	1.8	L;L;L;L;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.51	T
Polyphen		0.99	D;D;.;D;.;.
Vest4		0.58, 0.64
MutPred		0.50		Loss of stability (P = 0.019);Loss of stability (P = 0.019);Loss of stability (P = 0.019);Loss of stability (P = 0.019);Loss of stability (P = 0.019);Loss of stability (P = 0.019);
MVP		0.57
ClinPred		0.64	D
GERP RS		2.5
Varity_R		0.59
gMVP		0.36

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: rs1028088816; hg19: chr9-71650823;