rs398124308

Variant names:

• chr11-126275000-G-GGAGT
• rs398124308
• NM_017547.4:c.612_615dupAGTG

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_017547.4(FOXRED1):​c.612_615dupAGTG​(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 Likely pathogenic (★★). 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 3.28
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• mitochondrial complex I deficiency, nuclear type 19

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial complex I deficiency, nuclear type 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: Laboratory for Molecular Medicine, ClinGen
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex I deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 11-126275000-G-GGAGT is Pathogenic according to our data. Variant chr11-126275000-G-GGAGT is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 95754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017547.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXRED1	NM_017547.4	MANE Select	c.612_615dupAGTG	p.Ala206SerfsTer15	frameshift	Exon 5 of 11	NP_060017.1	Q96CU9-1
	FOXRED1	NM_001425160.1		c.642_645dupAGTG	p.Ala216SerfsTer15	frameshift	Exon 5 of 11	NP_001412089.1
	FOXRED1	NM_001425161.1		c.612_615dupAGTG	p.Ala206SerfsTer15	frameshift	Exon 5 of 11	NP_001412090.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXRED1	ENST00000263578.10	TSL:1 MANE Select	c.612_615dupAGTG	p.Ala206SerfsTer15	frameshift	Exon 5 of 11	ENSP00000263578.5	Q96CU9-1
	FOXRED1	ENST00000534315.5	TSL:1	n.944-325_944-322dupAGTG		intron	N/A
	FOXRED1	ENST00000853296.1		c.642_645dupAGTG	p.Ala216SerfsTer15	frameshift	Exon 5 of 11	ENSP00000523355.1

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152158 Hom.: 0 Cov.: 31

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

GnomAD2 exomes AF: 0.000227 AC: 57 AN: 251338 AF XY: 0.000206

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 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.: 0 Cov.: 30 AF XY: 0.000282 AC XY: 205 AN XY: 726824

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.000112 AC: 5 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000689 AC: 18 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000387 AC: 430 AN: 1111080

Other (OTH) AF: 0.000414 AC: 25 AN: 60370

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152276 Hom.: 0 Cov.: 31 AF XY: 0.000107 AC XY: 8 AN XY: 74468

African (AFR) AF: 0.0000963 AC: 4 AN: 41552

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000497 Hom.: 0

Bravo AF: 0.000178

EpiCase AF: 0.000273

EpiControl AF: 0.000415

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Mitochondrial complex I deficiency, nuclear type 19 (5)
5	-	-	not provided (5)
1	-	-	Inborn genetic diseases (1)
1	-	-	Leigh syndrome (1)
1	-	-	Mitochondrial complex I deficiency (1)
1	-	-	Mitochondrial complex I deficiency, nuclear type 1 (1)
1	-	-	Mitochondrial disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs398124308; hg19: chr11-126144895;