9-69035836-A-G

Variant names:

• chr9-69035836-A-G
• rs2481598
• NM_000144.5:c.54A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000144.5(FXN):​c.54A>G​(p.Pro18Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.997 in 1,511,616 control chromosomes in the GnomAD database, including 752,000 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (74033 hom., cov: 31)
  • Exomes 𝑓: 1.0 (677967 hom.)
• Consequence: FXN NM_000144.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.525
• Publications: 18 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 9-69035836-A-G is Benign according to our data. Variant chr9-69035836-A-G is described in ClinVar as Benign. ClinVar VariationId is 129120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.525 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000144.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FXN	NM_000144.5	MANE Select	c.54A>G	p.Pro18Pro	synonymous	Exon 1 of 5	NP_000135.2
	FXN	NM_181425.3		c.54A>G	p.Pro18Pro	synonymous	Exon 1 of 5	NP_852090.1	Q16595-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FXN	ENST00000484259.3	TSL:3 MANE Select	c.54A>G	p.Pro18Pro	synonymous	Exon 1 of 5	ENSP00000419243.2	Q16595-1
	ENSG00000285130	ENST00000642889.1		c.54A>G	p.Pro18Pro	synonymous	Exon 1 of 25	ENSP00000493780.1	A0A2R8YDH4
	ENSG00000285130	ENST00000646862.1		c.54A>G	p.Pro18Pro	synonymous	Exon 1 of 6	ENSP00000494599.1	A0A2R8Y577

Frequencies

GnomAD3 genomes AF: 0.986 AC: 149965 AN: 152050 Hom.: 73984 Cov.: 31

Gnomad AFR AF: 0.952

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.995

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.994

GnomAD2 exomes AF: 0.998 AC: 108411 AN: 108640 AF XY: 0.998

Gnomad AFR exome AF: 0.941

Gnomad AMR exome AF: 0.997

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.998

GnomAD4 exome AF: 0.999 AC: 1357658 AN: 1359454 Hom.: 677967 Cov.: 51 AF XY: 0.999 AC XY: 669689 AN XY: 670434

African (AFR) AF: 0.950 AC: 26957 AN: 28390

American (AMR) AF: 0.998 AC: 33794 AN: 33878

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 24392 AN: 24392

East Asian (EAS) AF: 1.00 AC: 33295 AN: 33296

South Asian (SAS) AF: 1.00 AC: 76537 AN: 76560

European-Finnish (FIN) AF: 1.00 AC: 33160 AN: 33160

Middle Eastern (MID) AF: 0.999 AC: 4028 AN: 4034

European-Non Finnish (NFE) AF: 1.00 AC: 1068874 AN: 1068978

Other (OTH) AF: 0.997 AC: 56621 AN: 56766

GnomAD4 genome AF: 0.986 AC: 150071 AN: 152162 Hom.: 74033 Cov.: 31 AF XY: 0.987 AC XY: 73401 AN XY: 74392

African (AFR) AF: 0.952 AC: 39547 AN: 41534

American (AMR) AF: 0.995 AC: 15226 AN: 15302

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5124 AN: 5124

South Asian (SAS) AF: 0.999 AC: 4829 AN: 4832

European-Finnish (FIN) AF: 1.00 AC: 10614 AN: 10614

Middle Eastern (MID) AF: 1.00 AC: 292 AN: 292

European-Non Finnish (NFE) AF: 1.00 AC: 67959 AN: 67972

Other (OTH) AF: 0.994 AC: 2096 AN: 2108

Alfa AF: 0.994 Hom.: 12725

Bravo AF: 0.985

Asia WGS AF: 0.997 AC: 3454 AN: 3466

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	not specified (4)
-	-	2	Friedreich ataxia 1 (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.6
DANN	Benign	0.49
PhyloP100		-0.53
PromoterAI		0.094	Neutral
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: rs2481598; hg19: chr9-71650752; COSMIC: COSV108220542; COSMIC: COSV108220542;