rs59907886

Positions:

• chr9-69046445-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1 BP6_Very_Strong BS1 BS2

The ENST00000377270.8(FXN):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00277 in 1,614,094 control chromosomes in the GnomAD database, including 110 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (57 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (53 hom.)
• Consequence: FXN ENST00000377270.8 start_lost
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.704

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• BP6: Variant 9-69046445-A-G is Benign according to our data. Variant chr9-69046445-A-G is described in ClinVar as [Benign]. Clinvar id is 263542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-69046445-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0148 (2260/152280) while in subpopulation AFR AF= 0.0507 (2107/41548). AF 95% confidence interval is 0.0489. There are 57 homozygotes in gnomad4. There are 1068 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 57 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FXN	NM_000144.5	c.226A>G	p.Met76Val	missense_variant	2/5	ENST00000484259.3
FXN	NM_181425.3	c.226A>G	p.Met76Val	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FXN	ENST00000484259.3	c.226A>G	p.Met76Val	missense_variant	2/5	3	NM_000144.5	P1

Frequencies

GnomAD3 genomes AF: 0.0148 AC: 2257 AN: 152162 Hom.: 57 Cov.: 32

Gnomad AFR AF: 0.0508

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00773

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00380 AC: 956 AN: 251386 Hom.: 20 AF XY: 0.00280 AC XY: 380 AN XY: 135858

Gnomad AFR exome AF: 0.0513

Gnomad AMR exome AF: 0.00266

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00151 AC: 2206 AN: 1461814 Hom.: 53 Cov.: 31 AF XY: 0.00134 AC XY: 976 AN XY: 727196

Gnomad4 AFR exome AF: 0.0519

Gnomad4 AMR exome AF: 0.00315

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000656

Gnomad4 OTH exome AF: 0.00386

GnomAD4 genome AF: 0.0148 AC: 2260 AN: 152280 Hom.: 57 Cov.: 32 AF XY: 0.0143 AC XY: 1068 AN XY: 74468

Gnomad4 AFR AF: 0.0507

Gnomad4 AMR AF: 0.00772

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00397 Hom.: 15

Bravo AF: 0.0171

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0433 AC: 191

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00450 AC: 546

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 08, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 29, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 18, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 22, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	9.4
DANN	Benign	0.39
DEOGEN2	Benign	0.31	T;.;.;T;T;T;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.53	.;T;T;T;.;D;T
MetaRNN	Benign	0.0028	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;L;L;L;.;.;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.76	.;N;N;.;N;N;.
REVEL	Benign	0.13
Sift	Benign	0.53	.;T;T;.;D;T;.
Sift4G	Benign	0.78	.;T;T;.;.;T;.
Polyphen		0.0010	B;B;.;B;.;.;.
Vest4		0.068, 0.085, 0.26
MVP		0.73
MPC		0.30
ClinPred		0.0013	T
GERP RS		1.1
Varity_R		0.10
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs59907886; hg19: chr9-71661361;