9-69073008-C-T

Variant names:

• chr9-69073008-C-T
• rs10890
• NM_000144.5:c.*246C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 15 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: G2P, Labcorp Genetics (formerly Invitae)
• Friedreich ataxia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285130 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
FXN	NM_000144.5	c.*246C>T		3_prime_UTR_variant	Exon 5 of 5	ENST00000484259.3	NP_000135.2
FXN	NM_181425.3	c.*296C>T		3_prime_UTR_variant	Exon 5 of 5		NP_852090.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FXN	ENST00000484259.3	c.*246C>T		3_prime_UTR_variant	Exon 5 of 5	3	NM_000144.5	ENSP00000419243.2
ENSG00000285130	ENST00000642889.1	c.166-26893C>T		intron_variant	Intron 1 of 24			ENSP00000493780.1

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

African (AFR) AF: 0.551 AC: 15317 AN: 27798

American (AMR) AF: 0.575 AC: 10949 AN: 19030

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 7457 AN: 18340

East Asian (EAS) AF: 0.624 AC: 20526 AN: 32918

South Asian (SAS) AF: 0.512 AC: 30791 AN: 60158

European-Finnish (FIN) AF: 0.421 AC: 11113 AN: 26404

Middle Eastern (MID) AF: 0.419 AC: 1464 AN: 3498

European-Non Finnish (NFE) AF: 0.462 AC: 471620 AN: 1020194

Other (OTH) AF: 0.487 AC: 25441 AN: 52194

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

African (AFR) AF: 0.555 AC: 22957 AN: 41386

American (AMR) AF: 0.540 AC: 8248 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.400 AC: 1388 AN: 3468

East Asian (EAS) AF: 0.644 AC: 3320 AN: 5154

South Asian (SAS) AF: 0.528 AC: 2545 AN: 4816

European-Finnish (FIN) AF: 0.404 AC: 4255 AN: 10524

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.450 AC: 30571 AN: 67950

Other (OTH) AF: 0.480 AC: 1010 AN: 2106

Alfa AF: 0.471 Hom.: 20807

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 18, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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