chr9-69035894-G-A

Position:

• chr9-69035894-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_000144.5(FXN):​c.112G>A​(p.Gly38Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000289 in 1,487,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: FXN NM_000144.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.71

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]

ENSG00000285130 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047568798).
• BP6: Variant 9-69035894-G-A is Benign according to our data. Variant chr9-69035894-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2515732.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FXN	NM_000144.5	c.112G>A	p.Gly38Ser	missense_variant	1/5	ENST00000484259.3	NP_000135.2
FXN	NM_181425.3	c.112G>A	p.Gly38Ser	missense_variant	1/5		NP_852090.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FXN	ENST00000484259.3	c.112G>A	p.Gly38Ser	missense_variant	1/5	3	NM_000144.5	ENSP00000419243.2
ENSG00000285130	ENST00000642889.1	c.112G>A	p.Gly38Ser	missense_variant	1/25			ENSP00000493780.1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 151824 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000532

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000150 AC: 20 AN: 1335852 Hom.: 0 Cov.: 36 AF XY: 0.0000121 AC XY: 8 AN XY: 658496

Gnomad4 AFR exome AF: 0.000593

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000720

GnomAD4 genome AF: 0.000151 AC: 23 AN: 151932 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74282

Gnomad4 AFR AF: 0.000530

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000227

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 02, 2023

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2023

This alteration is classified as likely 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	0.084
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	0.41
DANN	Benign	0.79
DEOGEN2	Benign	0.32	T;.;.;T;.;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.46	.;T;T;T;T;T
M_CAP	Pathogenic	0.75	D
MetaRNN	Benign	0.048	T;T;T;T;T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	0.85	L;L;L;L;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.10	.;N;N;.;.;.
REVEL	Benign	0.18
Sift	Benign	0.26	.;T;T;.;.;.
Sift4G	Benign	0.32	.;T;T;.;.;.
Polyphen		0.0030	B;B;.;B;.;.
Vest4		0.053, 0.12
MutPred		0.44		Gain of glycosylation at G38 (P = 0.0152);Gain of glycosylation at G38 (P = 0.0152);Gain of glycosylation at G38 (P = 0.0152);Gain of glycosylation at G38 (P = 0.0152);Gain of glycosylation at G38 (P = 0.0152);Gain of glycosylation at G38 (P = 0.0152);
MVP		0.50
ClinPred		0.095	T
GERP RS		-0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.047
gMVP		0.20

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

Publications

LitVar

Other links and lift over

dbSNP: rs576852565; hg19: chr9-71650810;