11-126269216-A-G
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting
The NM_017547.4(FOXRED1):āc.10A>Gā(p.Arg4Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000676 in 1,613,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_017547.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000112 AC: 17AN: 152238Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.000128 AC: 32AN: 250210Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135594
GnomAD4 exome AF: 0.0000630 AC: 92AN: 1461184Hom.: 0 Cov.: 37 AF XY: 0.0000688 AC XY: 50AN XY: 726954
GnomAD4 genome AF: 0.000112 AC: 17AN: 152356Hom.: 0 Cov.: 34 AF XY: 0.000121 AC XY: 9AN XY: 74502
ClinVar
Submissions by phenotype
not provided Uncertain:2
In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 4 of the FOXRED1 protein (p.Arg4Gly). This variant is present in population databases (rs149883459, gnomAD 0.2%). This missense change has been observed in individual(s) with FOXRED1-related conditions (PMID: 36307859). ClinVar contains an entry for this variant (Variation ID: 214439). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The glycine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Mitochondrial complex I deficiency, nuclear type 1 Uncertain:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at