9-69035776-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000144.5(FXN):c.-7G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0285 in 1,503,062 control chromosomes in the GnomAD database, including 744 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (49 hom., cov: 33)
  • Exomes 𝑓: 0.029 (695 hom.)
• Consequence: FXN NM_000144.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.992

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 9-69035776-G-A is Benign according to our data. Variant chr9-69035776-G-A is described in ClinVar as [Benign]. Clinvar id is 193050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-69035776-G-A is described in Lovd as [Likely_benign]. Variant chr9-69035776-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0204 (3110/152282) while in subpopulation NFE AF= 0.0319 (2170/68008). AF 95% confidence interval is 0.0308. There are 49 homozygotes in gnomad4. There are 1463 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 49 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FXN	NM_000144.5	c.-7G>A		5_prime_UTR_variant	1/5	ENST00000484259.3
FXN	NM_181425.3	c.-7G>A		5_prime_UTR_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FXN	ENST00000484259.3	c.-7G>A		5_prime_UTR_variant	1/5	3	NM_000144.5	P1

Frequencies

GnomAD3 genomes AF: 0.0204 AC: 3109 AN: 152164 Hom.: 49 Cov.: 33

Gnomad AFR AF: 0.00680

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.0207

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.0137

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0319

Gnomad OTH AF: 0.0230

GnomAD3 exomes AF: 0.0198 AC: 2106 AN: 106146 Hom.: 44 AF XY: 0.0195 AC XY: 1148 AN XY: 58766

Gnomad AFR exome AF: 0.00549

Gnomad AMR exome AF: 0.0182

Gnomad ASJ exome AF: 0.0226

Gnomad EAS exome AF: 0.000133

Gnomad SAS exome AF: 0.00488

Gnomad FIN exome AF: 0.0133

Gnomad NFE exome AF: 0.0327

Gnomad OTH exome AF: 0.0235

GnomAD4 exome AF: 0.0294 AC: 39729 AN: 1350780 Hom.: 695 Cov.: 29 AF XY: 0.0285 AC XY: 18966 AN XY: 665604

Gnomad4 AFR exome AF: 0.00481

Gnomad4 AMR exome AF: 0.0177

Gnomad4 ASJ exome AF: 0.0223

Gnomad4 EAS exome AF: 0.000397

Gnomad4 SAS exome AF: 0.00466

Gnomad4 FIN exome AF: 0.0151

Gnomad4 NFE exome AF: 0.0338

Gnomad4 OTH exome AF: 0.0279

GnomAD4 genome AF: 0.0204 AC: 3110 AN: 152282 Hom.: 49 Cov.: 33 AF XY: 0.0196 AC XY: 1463 AN XY: 74462

Gnomad4 AFR AF: 0.00678

Gnomad4 AMR AF: 0.0207

Gnomad4 ASJ AF: 0.0248

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00455

Gnomad4 FIN AF: 0.0137

Gnomad4 NFE AF: 0.0319

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.0234 Hom.: 10

Bravo AF: 0.0205

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 17, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 21, 2019	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	2.2
Dann	Benign	0.82

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: rs145006100; hg19: chr9-71650692;