rs145006100

Variant names:

• chr9-69035776-G-A
• rs145006100
• NM_000144.5:c.-7G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-69035776-G-A
• chr9-69035776-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000144.5(FXN):​c.-7G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0285 in 1,503,062 control chromosomes in the GnomAD database, including 744 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (49 hom., cov: 33)
  • Exomes 𝑓: 0.029 (695 hom.)
• Consequence: FXN NM_000144.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.992
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 9-69035776-G-A is Benign according to our data. Variant chr9-69035776-G-A is described in ClinVar as Benign. ClinVar VariationId is 193050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0204 (3110/152282) while in subpopulation NFE AF = 0.0319 (2170/68008). AF 95% confidence interval is 0.0308. There are 49 homozygotes in GnomAd4. There are 1463 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 49 AR gene

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.-7G>A		5_prime_UTR	Exon 1 of 5	NP_000135.2
	FXN	NM_181425.3		c.-7G>A		5_prime_UTR	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.-7G>A		5_prime_UTR	Exon 1 of 5	ENSP00000419243.2	Q16595-1
	ENSG00000285130	ENST00000642889.1		c.-7G>A		5_prime_UTR	Exon 1 of 25	ENSP00000493780.1	A0A2R8YDH4
	ENSG00000285130	ENST00000646862.1		c.-7G>A		5_prime_UTR	Exon 1 of 6	ENSP00000494599.1	A0A2R8Y577

Frequencies

GnomAD3 genomes AF: 0.0204 AC: 3109 AN: 152164 Hom.: 49 Cov.: 33

Gnomad AFR AF: 0.00680

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.0207

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.0137

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0319

Gnomad OTH AF: 0.0230

GnomAD2 exomes AF: 0.0198 AC: 2106 AN: 106146 AF XY: 0.0195

Gnomad AFR exome AF: 0.00549

Gnomad AMR exome AF: 0.0182

Gnomad ASJ exome AF: 0.0226

Gnomad EAS exome AF: 0.000133

Gnomad FIN exome AF: 0.0133

Gnomad NFE exome AF: 0.0327

Gnomad OTH exome AF: 0.0235

GnomAD4 exome AF: 0.0294 AC: 39729 AN: 1350780 Hom.: 695 Cov.: 29 AF XY: 0.0285 AC XY: 18966 AN XY: 665604

African (AFR) AF: 0.00481 AC: 136 AN: 28288

American (AMR) AF: 0.0177 AC: 587 AN: 33104

Ashkenazi Jewish (ASJ) AF: 0.0223 AC: 538 AN: 24156

East Asian (EAS) AF: 0.000397 AC: 13 AN: 32758

South Asian (SAS) AF: 0.00466 AC: 353 AN: 75670

European-Finnish (FIN) AF: 0.0151 AC: 494 AN: 32648

Middle Eastern (MID) AF: 0.0100 AC: 40 AN: 3986

European-Non Finnish (NFE) AF: 0.0338 AC: 35993 AN: 1063810

Other (OTH) AF: 0.0279 AC: 1575 AN: 56360

GnomAD4 genome AF: 0.0204 AC: 3110 AN: 152282 Hom.: 49 Cov.: 33 AF XY: 0.0196 AC XY: 1463 AN XY: 74462

African (AFR) AF: 0.00678 AC: 282 AN: 41568

American (AMR) AF: 0.0207 AC: 317 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 86 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00455 AC: 22 AN: 4830

European-Finnish (FIN) AF: 0.0137 AC: 145 AN: 10608

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.0319 AC: 2170 AN: 68008

Other (OTH) AF: 0.0227 AC: 48 AN: 2112

Alfa AF: 0.0234 Hom.: 10

Bravo AF: 0.0205

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	2.2
DANN	Benign	0.82
PhyloP100		-0.99
PromoterAI		-0.078	Neutral
Mutation Taster		=300/0	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: rs145006100; hg19: chr9-71650692;