NM_000144.5:c.384+4857G>A

Variant names:

• chr9-69058117-G-A
• rs3793456
• NM_000144.5:c.384+4857G>A

Variant summary

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

The NM_000144.5(FXN):​c.384+4857G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.377 in 152,054 control chromosomes in the GnomAD database, including 11,440 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 0.38 (11440 hom., cov: 32)
• Consequence: FXN NM_000144.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.153
• Publications: 5 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=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.428 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FXN	NM_000144.5	c.384+4857G>A		intron_variant	Intron 3 of 4	ENST00000484259.3	NP_000135.2
FXN	NM_181425.3	c.384+4857G>A		intron_variant	Intron 3 of 4		NP_852090.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FXN	ENST00000484259.3	c.384+4857G>A		intron_variant	Intron 3 of 4	3	NM_000144.5	ENSP00000419243.2
ENSG00000285130	ENST00000642889.1	c.165+22170G>A		intron_variant	Intron 1 of 24			ENSP00000493780.1

Frequencies

GnomAD3 genomes AF: 0.377 AC: 57231 AN: 151936 Hom.: 11436 Cov.: 32

Gnomad AFR AF: 0.242

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.393

Gnomad ASJ AF: 0.403

Gnomad EAS AF: 0.362

Gnomad SAS AF: 0.374

Gnomad FIN AF: 0.534

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.433

Gnomad OTH AF: 0.391

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

GnomAD4 genome AF: 0.377 AC: 57256 AN: 152054 Hom.: 11440 Cov.: 32 AF XY: 0.381 AC XY: 28281 AN XY: 74318

African (AFR) AF: 0.242 AC: 10026 AN: 41494

American (AMR) AF: 0.393 AC: 6004 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.403 AC: 1400 AN: 3472

East Asian (EAS) AF: 0.362 AC: 1871 AN: 5170

South Asian (SAS) AF: 0.374 AC: 1797 AN: 4806

European-Finnish (FIN) AF: 0.534 AC: 5639 AN: 10560

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.432 AC: 29394 AN: 67964

Other (OTH) AF: 0.396 AC: 836 AN: 2112

Alfa AF: 0.407 Hom.: 7763

Bravo AF: 0.358

Asia WGS AF: 0.389 AC: 1352 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.9
DANN	Benign	0.67
PhyloP100		0.15
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: rs3793456; hg19: chr9-71673033;