rs387907087
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_017547.4(FOXRED1):c.1054C>T(p.Arg352Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000808 in 1,608,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R352R) has been classified as Likely benign.
Frequency
Consequence
NM_017547.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FOXRED1 | NM_017547.4 | c.1054C>T | p.Arg352Trp | missense_variant | 9/11 | ENST00000263578.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FOXRED1 | ENST00000263578.10 | c.1054C>T | p.Arg352Trp | missense_variant | 9/11 | 1 | NM_017547.4 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000133 AC: 2AN: 150916Hom.: 0 Cov.: 29
GnomAD3 exomes AF: 0.0000240 AC: 6AN: 250006Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135548
GnomAD4 exome AF: 0.00000755 AC: 11AN: 1457566Hom.: 0 Cov.: 34 AF XY: 0.00000552 AC XY: 4AN XY: 725112
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 151034Hom.: 0 Cov.: 29 AF XY: 0.0000136 AC XY: 1AN XY: 73736
ClinVar
Submissions by phenotype
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 13, 2017 | - - |
Mitochondrial complex 1 deficiency, nuclear type 19 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 15, 2010 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 352 of the FOXRED1 protein (p.Arg352Trp). This variant is present in population databases (rs387907087, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of mitochondrial complex I deficiency (PMID: 20858599, 33613441). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 31048). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FOXRED1 protein function. Studies have shown that this missense change alters FOXRED1 gene expression (PMID: 20858599). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at