11-126275022-GG-CA

Variant names:

• chr11-126275022-GT-CA
• NM_017547.4:c.631+1_631+2delGTinsCA

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_017547.4(FOXRED1):​c.631+1_631+2delGTinsCA variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: FOXRED1 NM_017547.4 splice_donor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.88
• Publications: 0 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: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

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.631+1_631+2delGTinsCA		splice_donor intron	N/A	NP_060017.1	Q96CU9-1
	FOXRED1	NM_001425160.1		c.661+1_661+2delGTinsCA		splice_donor intron	N/A	NP_001412089.1
	FOXRED1	NM_001425161.1		c.631+1_631+2delGTinsCA		splice_donor intron	N/A	NP_001412090.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXRED1	ENST00000263578.10	TSL:1 MANE Select	c.631+1_631+2delGTinsCA		splice_donor intron	N/A	ENSP00000263578.5	Q96CU9-1
	FOXRED1	ENST00000534315.5	TSL:1	n.944-305_944-304delGTinsCA		intron	N/A
	FOXRED1	ENST00000853296.1		c.661+1_661+2delGTinsCA		splice_donor intron	N/A	ENSP00000523355.1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.9

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr11-126144917;