rs148346044

chr11-126271475-A-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.579

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 -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: {Benign=2, Likely_benign=3, Uncertain_significance=1}. 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 GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXRED1	NM_017547.4	c.124A>C	p.Lys42Gln	missense_variant	2/11	ENST00000263578.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXRED1	ENST00000263578.10	c.124A>C	p.Lys42Gln	missense_variant	2/11	1	NM_017547.4	P3

Frequencies

GnomAD3 genomes AF: 0.00286 AC: 436 AN: 152222 Hom.: 1 Cov.: 32

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.: 2 AF XY: 0.00254 AC XY: 345 AN XY: 135920

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.: 21 Cov.: 31 AF XY: 0.00419 AC XY: 3048 AN XY: 727198

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.: 1 Cov.: 32 AF XY: 0.00258 AC XY: 192 AN XY: 74504

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.: 7

Bravo AF: 0.00270

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00465 AC: 40

ExAC AF: 0.00290 AC: 352

EpiCase AF: 0.00398

EpiControl AF: 0.00356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

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

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 21, 2016	- -
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. -

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	T
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	N
LIST_S2	Benign	0.45	T;T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.0031	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.60	N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.24	T
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	T
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

Other links and lift over

dbSNP: rs148346044; hg19: chr11-126141370; COSMIC: COSV99703236; COSMIC: COSV99703236;