9-69044364-C-T

Variant names:

• chr9-69044364-C-T
• rs3793451
• NM_000144.5:c.166-2021C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000144.5(FXN):​c.166-2021C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0648 in 152,250 control chromosomes in the GnomAD database, including 569 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.065 (569 hom., cov: 32)
• Consequence: FXN NM_000144.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0150
• Publications: 12 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FXN	NM_000144.5	c.166-2021C>T		intron_variant	Intron 1 of 4	ENST00000484259.3	NP_000135.2
FXN	NM_181425.3	c.166-2021C>T		intron_variant	Intron 1 of 4		NP_852090.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FXN	ENST00000484259.3	c.166-2021C>T		intron_variant	Intron 1 of 4	3	NM_000144.5	ENSP00000419243.2
ENSG00000285130	ENST00000642889.1	c.165+8417C>T		intron_variant	Intron 1 of 24			ENSP00000493780.1

Frequencies

GnomAD3 genomes AF: 0.0648 AC: 9864 AN: 152132 Hom.: 567 Cov.: 32

Gnomad AFR AF: 0.0419

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.0559

Gnomad EAS AF: 0.251

Gnomad SAS AF: 0.0861

Gnomad FIN AF: 0.0271

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0443

Gnomad OTH AF: 0.0794

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0648 AC: 9871 AN: 152250 Hom.: 569 Cov.: 32 AF XY: 0.0663 AC XY: 4936 AN XY: 74448

African (AFR) AF: 0.0418 AC: 1738 AN: 41566

American (AMR) AF: 0.176 AC: 2682 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0559 AC: 194 AN: 3468

East Asian (EAS) AF: 0.251 AC: 1297 AN: 5160

South Asian (SAS) AF: 0.0849 AC: 410 AN: 4828

European-Finnish (FIN) AF: 0.0271 AC: 288 AN: 10620

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0443 AC: 3014 AN: 68010

Other (OTH) AF: 0.0810 AC: 171 AN: 2112

Alfa AF: 0.0619 Hom.: 1416

Bravo AF: 0.0808

Asia WGS AF: 0.181 AC: 630 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.3
DANN	Benign	0.89
PhyloP100		0.015
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: rs3793451; hg19: chr9-71659280;