rs148346044

Positions:

chr11-126271475-A-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_017547.4(FOXRED1):c.124A>C(p.Lys42Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00421 in 1,614,136 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.0029 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0043 ( 21 hom. )

Consequence

FOXRED1
NM_017547.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 0.579

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:

FOXRED1 (HGNC:):

FOXRED1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003114462).

BP6

Variant 11-126271475-A-C is Benign according to our data. Variant chr11-126271475-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 129112.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=2}. Variant chr11-126271475-A-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00286 (436/152340) while in subpopulation NFE AF= 0.00503 (342/68028). AF 95% confidence interval is 0.00459. There are 1 homozygotes in gnomad4. There are 192 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXRED1	NM_017547.4 linkuse as main transcript	c.124A>C	p.Lys42Gln	missense_variant	2/11	ENST00000263578.10	NP_060017.1	Q96CU9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXRED1	ENST00000263578.10 linkuse as main transcript	c.124A>C	p.Lys42Gln	missense_variant	2/11	1	NM_017547.4	ENSP00000263578.5		Q96CU9-1

Frequencies

GnomAD3 genomes

AF:

0.00286

AC:

436

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000699

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00209

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00503

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00259

AC:

651

AN:

251486

Hom.:

AF XY:

0.00254

AC XY:

345

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.000861

Gnomad AMR exome

AF:

0.000925

Gnomad ASJ exome

AF:

0.00278

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.00194

Gnomad NFE exome

AF:

0.00454

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00435

AC:

6353

AN:

1461796

Hom.:

Cov.:

AF XY:

0.00419

AC XY:

3048

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.000627

Gnomad4 AMR exome

AF:

0.00112

Gnomad4 ASJ exome

AF:

0.00363

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000336

Gnomad4 FIN exome

AF:

0.00234

Gnomad4 NFE exome

AF:

0.00524

Gnomad4 OTH exome

AF:

0.00329

GnomAD4 genome

AF:

0.00286

AC:

436

AN:

152340

Hom.:

Cov.:

AF XY:

0.00258

AC XY:

192

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.000697

Gnomad4 AMR

AF:

0.00209

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00151

Gnomad4 NFE

AF:

0.00503

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00445

Hom.:

Bravo

AF:

0.00270

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00465

AC:

ExAC

AF:

0.00290

AC:

352

EpiCase

AF:

0.00398

EpiControl

AF:

0.00356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	FOXRED1: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 05, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 21, 2016	- -

Mitochondrial complex I deficiency, nuclear type 1

Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.66

CADD

Benign

3.4

DANN

Benign

0.60

DEOGEN2

Benign

0.0067

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.45

T;T

M_CAP

Benign

0.0053

MetaRNN

Benign

0.0031

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.60

N;.

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.42

N;N

REVEL

Benign

0.062

Sift

Benign

0.70

T;T

Sift4G

Benign

0.52

T;T

Polyphen

0.0010

B;B

Vest4

0.14

MVP

0.14

MPC

0.17

ClinPred

0.00085

GERP RS

0.25

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.031

gMVP

0.44

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

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