11-126269205-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017547.4(FOXRED1):c.-2T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.773 in 1,608,530 control chromosomes in the GnomAD database, including 484,374 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (41357 hom., cov: 36)
  • Exomes 𝑓: 0.78 (443017 hom.)
• Consequence: FOXRED1 NM_017547.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.699

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 11-126269205-T-C is Benign according to our data. Variant chr11-126269205-T-C is described in ClinVar as [Benign]. Clinvar id is 303532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-126269205-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXRED1	NM_017547.4	c.-2T>C		5_prime_UTR_variant	1/11	ENST00000263578.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXRED1	ENST00000263578.10	c.-2T>C		5_prime_UTR_variant	1/11	1	NM_017547.4	P3

Frequencies

GnomAD3 genomes AF: 0.728 AC: 110672 AN: 152118 Hom.: 41320 Cov.: 36

Gnomad AFR AF: 0.562

Gnomad AMI AF: 0.766

Gnomad AMR AF: 0.800

Gnomad ASJ AF: 0.749

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.890

Gnomad FIN AF: 0.799

Gnomad MID AF: 0.693

Gnomad NFE AF: 0.768

Gnomad OTH AF: 0.720

GnomAD3 exomes AF: 0.796 AC: 198960 AN: 249968 Hom.: 80411 AF XY: 0.798 AC XY: 108147 AN XY: 135490

Gnomad AFR exome AF: 0.554

Gnomad AMR exome AF: 0.863

Gnomad ASJ exome AF: 0.751

Gnomad EAS exome AF: 0.999

Gnomad SAS exome AF: 0.882

Gnomad FIN exome AF: 0.782

Gnomad NFE exome AF: 0.761

Gnomad OTH exome AF: 0.779

GnomAD4 exome AF: 0.777 AC: 1131976 AN: 1456296 Hom.: 443017 Cov.: 37 AF XY: 0.781 AC XY: 565813 AN XY: 724758

Gnomad4 AFR exome AF: 0.543

Gnomad4 AMR exome AF: 0.851

Gnomad4 ASJ exome AF: 0.754

Gnomad4 EAS exome AF: 0.999

Gnomad4 SAS exome AF: 0.879

Gnomad4 FIN exome AF: 0.779

Gnomad4 NFE exome AF: 0.766

Gnomad4 OTH exome AF: 0.775

GnomAD4 genome AF: 0.728 AC: 110760 AN: 152234 Hom.: 41357 Cov.: 36 AF XY: 0.738 AC XY: 54940 AN XY: 74430

Gnomad4 AFR AF: 0.563

Gnomad4 AMR AF: 0.800

Gnomad4 ASJ AF: 0.749

Gnomad4 EAS AF: 0.997

Gnomad4 SAS AF: 0.889

Gnomad4 FIN AF: 0.799

Gnomad4 NFE AF: 0.768

Gnomad4 OTH AF: 0.724

Alfa AF: 0.752 Hom.: 53494

Bravo AF: 0.717

Asia WGS AF: 0.921 AC: 3203 AN: 3478

EpiCase AF: 0.759

EpiControl AF: 0.753

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 15, 2016	- -

Mitochondrial complex I deficiency, nuclear type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Mitochondrial complex 1 deficiency, nuclear type 19 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	5.4
Dann	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1786702; hg19: chr11-126139100;