chr9-69073008-C-T

Position:

• chr9-69073008-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000144.5(FXN):​c.*246C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.474 in 1,412,404 control chromosomes in the GnomAD database, including 160,872 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (18850 hom., cov: 32)
  • Exomes 𝑓: 0.47 (142022 hom.)
• Consequence: FXN NM_000144.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.547

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=-0.9).
• BP6: Variant 9-69073008-C-T is Benign according to our data. Variant chr9-69073008-C-T is described in ClinVar as [Benign]. Clinvar id is 1222153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.626 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FXN	NM_000144.5	c.*246C>T		3_prime_UTR_variant	5/5	ENST00000484259.3	NP_000135.2
FXN	NM_181425.3	c.*296C>T		3_prime_UTR_variant	5/5		NP_852090.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FXN	ENST00000484259.3	c.*246C>T		3_prime_UTR_variant	5/5	3	NM_000144.5	ENSP00000419243	P1

Frequencies

GnomAD3 genomes AF: 0.494 AC: 74918 AN: 151752 Hom.: 18833 Cov.: 32

Gnomad AFR AF: 0.555

Gnomad AMI AF: 0.623

Gnomad AMR AF: 0.540

Gnomad ASJ AF: 0.400

Gnomad EAS AF: 0.644

Gnomad SAS AF: 0.529

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.450

Gnomad OTH AF: 0.482

GnomAD4 exome AF: 0.472 AC: 594678 AN: 1260534 Hom.: 142022 Cov.: 32 AF XY: 0.472 AC XY: 288431 AN XY: 610922

Gnomad4 AFR exome AF: 0.551

Gnomad4 AMR exome AF: 0.575

Gnomad4 ASJ exome AF: 0.407

Gnomad4 EAS exome AF: 0.624

Gnomad4 SAS exome AF: 0.512

Gnomad4 FIN exome AF: 0.421

Gnomad4 NFE exome AF: 0.462

Gnomad4 OTH exome AF: 0.487

GnomAD4 genome AF: 0.494 AC: 74982 AN: 151870 Hom.: 18850 Cov.: 32 AF XY: 0.496 AC XY: 36816 AN XY: 74210

Gnomad4 AFR AF: 0.555

Gnomad4 AMR AF: 0.540

Gnomad4 ASJ AF: 0.400

Gnomad4 EAS AF: 0.644

Gnomad4 SAS AF: 0.528

Gnomad4 FIN AF: 0.404

Gnomad4 NFE AF: 0.450

Gnomad4 OTH AF: 0.480

Alfa AF: 0.466 Hom.: 15344

Bravo AF: 0.510

Asia WGS AF: 0.557 AC: 1939 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2021	This variant is associated with the following publications: (PMID: 18682748) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.2
DANN	Benign	0.40
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs10890; hg19: chr9-71687924; COSMIC: COSV66009512;