rs797045091

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_017547.4(FOXRED1):c.612_615dup(p.Ala206SerfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000311 in 1,613,142 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00033 ( 0 hom. )

Consequence

FOXRED1
NM_017547.4 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:13U:1

Conservation

PhyloP100: 3.28

Variant links:

Genes affected

FOXRED1 (HGNC:26927): (FAD dependent oxidoreductase domain containing 1) This gene encodes a protein that contains a FAD-dependent oxidoreductase domain. The encoded protein is localized to the mitochondria and may function as a chaperone protein required for the function of mitochondrial complex I. Mutations in this gene are associated with mitochondrial complex I deficiency. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Dec 2010]

FOXRED1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-126275000-G-GGAGT is Pathogenic according to our data. Variant chr11-126275000-G-GGAGT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95754.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=11, Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXRED1	NM_017547.4 linkuse as main transcript	c.612_615dup	p.Ala206SerfsTer15	frameshift_variant	5/11	ENST00000263578.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXRED1	ENST00000263578.10 linkuse as main transcript	c.612_615dup	p.Ala206SerfsTer15	frameshift_variant	5/11	1	NM_017547.4	P3	Q96CU9-1

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000235

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000227

AC:

AN:

251338

Hom.:

AF XY:

0.000206

AC XY:

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.000794

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000370

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000330

AC:

482

AN:

1460866

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

205

AN XY:

726824

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.000689

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.000387

Gnomad4 OTH exome

AF:

0.000414

GnomAD4 genome

AF:

0.000131

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000497

Hom.:

Bravo

AF:

0.000178

EpiCase

AF:

0.000273

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:13Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2023	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22200994, 30956948, 31589614, 33613441, 30723688, 31065540) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	This sequence change creates a premature translational stop signal (p.Ala206Serfs*15) in the FOXRED1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FOXRED1 are known to be pathogenic (PMID: 20818383, 20858599). This variant is present in population databases (rs765593341, gnomAD 0.07%). This premature translational stop signal has been observed in individuals with mitochondrial complex I deficiency (PMID: 22200994, 31065540). ClinVar contains an entry for this variant (Variation ID: 95754). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 12, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2017	- -

Mitochondrial complex 1 deficiency, nuclear type 19

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 16, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5. -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	May 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 24, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Apr 20, 2022	- -

Mitochondrial complex I deficiency, nuclear type 1

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 22, 2017	The FOXRED1 c.612_615dupAGTG (p.Ala206SerfsTer15) variant results in a frameshift variant predicted to result in premature termination of the protein. The p.Ala206SerfsTer15 variant has been reported in one individual with mitochondrial complex I deficiency in a compound heterozygous state with a known likely pathogenic missense variant (Haack et al. 2012). The age of onset of disease in this individual was before six months of age, with the disease course described as progressive. The individual was reported to have less than 25% of complex 1 activity compared to controls. The p.Ala206SerfsTer15 variant was also identified in one healthy individual in a heterozygous state (Vassy et al. 2017). The p.Ala206SerfsTer15 variant was absent from 200 control chromosomes and is reported at a frequency of 0.00069 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the evidence and the potential impact of frameshift variants, the p.Ala206SerfsTer15 variant is classified as a variant of unknown significance but suspicious for pathogenicity for mitochondrial complex I deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.612_615dup;p.(Ala206Serfs15) is a null frameshift variant (NMD) in the FOXRED1 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevantexon to the transcript -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 95754; PMID: 33613441; 31065540; 22200994; 30723688; 30956948; 31589614) - PS4. The variant is present at low allele frequencies population databases (rs398124308– gnomAD 0.01314%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Ala206Serfs15) was detected in trans with a pathogenic variant(PMID: 22200994, 30723688, 31065540) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic. -

Mitochondrial complex I deficiency

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 08, 2014

The Ala206SerfsX15 variant has been identified in 0.012% (1/8254) of European American chromosomes and 0.023% (1/4264) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). The same frameshift variant (but from a different nucleotide variant) in FOXRED1 has been reported in 1 individual with mitochondrial complex I deficiency (Haack 2012). This individual was compound heterozygous. The Ala206SerfsX15 frameshift variant is predicted to alter the protein’s amino acid sequence beginning at position 206 and lead to a premature termination codon 15 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant is likely to be pathogenic, though additional data are required to fully establish the role of the FOXRED1 gene in disease given limited studies to date. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 25, 2022

The c.612_615dupAGTG (p.A206Sfs*15) alteration, located in exon 5 (coding exon 5) of the FOXRED1 gene, consists of a duplication of AGTG at position 612, causing a translational frameshift with a predicted alternate stop codon after 15 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration has been detected with another mutation in patients with FOXRED1-related mitochondrial complex I deficiency (Ahmed, 2017; Apatean, 2019; Haack, 2012). Based on the available evidence, this alteration is classified as pathogenic. -

Leigh syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 24, 2016

Variant summary: The FOXRED1 c.612_615dupAGTG (p.Ala206Serfs) variant results in a premature termination codon, predicted to cause a truncated or absent FOXRED1 protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. If NMD is escaped, this variant is predicted to truncate Glycine/D-amino acid oxidase domain. Truncation downstream of this position has also been reported (PMID: 20818383). This variant was found in 24/120958 control chromosomes at a frequency of 0.0001984, which does not exceed the estimated maximal expected allele frequency of a pathogenic FOXRED1 variant (0.00125). This variant has been reported in literature in one patient with mitochondrial complex I deficiency in compound heterozygous state with p.R136W variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over