rs61733203
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1PM2PP2BP4_Moderate
The NM_014874.4(MFN2):c.160G>A(p.Ala54Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000083 in 1,613,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A54V) has been classified as Uncertain significance.
Frequency
Consequence
NM_014874.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000789 AC: 12AN: 152044Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251324Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135848
GnomAD4 exome AF: 0.0000835 AC: 122AN: 1461768Hom.: 0 Cov.: 31 AF XY: 0.0000715 AC XY: 52AN XY: 727190
GnomAD4 genome AF: 0.0000789 AC: 12AN: 152044Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74258
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:1
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MFN2: PM2 -
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The p.Ala54Thr variant (rs61733203) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.003 percent (identified on 9 out of 277,100 chromosomes) and has been reported to the ClinVar database as variant of uncertain significance (Variation ID: 214657). The alanine at position 54 is moderately conserved considering 11 species (Alamut v2.10) and computational analyses of the effects of the p.Ala54Thr variant on protein structure and function provide conflicting results (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2:benign). Altogether, there is not enough evidence to classify the p.Ala54Thr variant with certainty. -
Inborn genetic diseases Uncertain:1
The p.A54T variant (also known as c.160G>A), located in coding exon 1 of the MFN2 gene, results from a G to A substitution at nucleotide position 160. The alanine at codon 54 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Charcot-Marie-Tooth disease type 2 Uncertain:1
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 54 of the MFN2 protein (p.Ala54Thr). This variant is present in population databases (rs61733203, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with MFN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 214657). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The threonine 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at