18-60371544-A-T
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PP3PP5BP4BS1_SupportingBS2_Supporting
The NM_005912.3(MC4R):c.806T>A(p.Ile269Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000192 in 1,614,220 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_005912.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MC4R | ENST00000299766.5 | c.806T>A | p.Ile269Asn | missense_variant | Exon 1 of 1 | 6 | NM_005912.3 | ENSP00000299766.3 | ||
ENSG00000285681 | ENST00000650201.1 | n.113+42199A>T | intron_variant | Intron 1 of 3 | ||||||
ENSG00000285681 | ENST00000658928.1 | n.156+42199A>T | intron_variant | Intron 1 of 3 |
Frequencies
GnomAD3 genomes AF: 0.000105 AC: 16AN: 152230Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00103 AC: 259AN: 251352Hom.: 5 AF XY: 0.000707 AC XY: 96AN XY: 135836
GnomAD4 exome AF: 0.000201 AC: 294AN: 1461872Hom.: 4 Cov.: 31 AF XY: 0.000162 AC XY: 118AN XY: 727240
GnomAD4 genome AF: 0.000105 AC: 16AN: 152348Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5AN XY: 74498
ClinVar
Submissions by phenotype
BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20 Pathogenic:2Uncertain:1
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not provided Pathogenic:1Uncertain:2
This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 269 of the MC4R protein (p.Ile269Asn). This variant is present in population databases (rs79783591, gnomAD 0.7%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with obesity (PMID: 19091795, 19889825, 30811542, 31841602, 35562395). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36486). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MC4R protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects MC4R function (PMID: 22106157, 24276017, 25332687, 31002796). 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. -
Although the frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene, this variant was shown to associate with obesity in Mexican children and adults (PMID:31841602, http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments showed reduced cell surface expression and ligand binding, as well as loss of signal transduction (PMID:18801902,24276017,31002796). Computational tools predict that this variant is damaging. -
Identified in multiple individuals with obesity but it is unknown whether these individuals were screened for variants in other genes associated with obesity (PMID: 18801902, 30811542, 35562395, 31841602); Reported as a founder variant for obesity among individuals of Mexican background (PMID: 31841602); Published functional studies demonstrate a damaging effect (PMID: 31002796); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17628007, 19091795, 22106157, 31002796, 25332687, 33045043, 18801902, 30811542, 35562395, 31841602, 31118516, 33542413, 35460704) -
Obesity Pathogenic:1Uncertain:1
The p.Ile269Asn variant in MC4R has been reported in 4 individuals with Obesity (PMID: 18801902, 19091795), and has been identified in 0.7309% (259/35438) of Latino chromosomes, including 5 homozygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs79783591). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported as a VUS, likely pathogenic variant, and a pathogenic variant in ClinVar (Variation ID: 36486). In vitro functional studies provide some evidence that the p.Ile269Asn variant may impact cell surface expression, protein folding, and receptor activation (PMID: 18801902, 19091795). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS3, PS4_Supporting (Richards 2015). -
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not specified Uncertain:2
Variant summary: MC4R c.806T>A (p.Ile269Asn) results in a non-conservative amino acid change located in the GPCR, rhodopsin-like, 7TM domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00092 in 277298 control chromosomes, predominantly at a frequency of 0.0073 within the Latino subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 15 fold of the estimated maximal expected allele frequency for a pathogenic variant in MC4R causing Early Onset Obesity phenotype (0.0005), suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. However, c.806T>A has been reported in the literature in multiple individuals affected with Early Onset Obesity (Hohenadel_2014, Tan_2009). Furthermore, at-least two of these reports identified this variant in individuals of Hispanic/Latina ancestry who are enriched for this variant among the control cohorts. These reports do not provide unequivocal conclusions about association of the variant with Early Onset Obesity. Experimental evidence evaluating an impact on protein function demonstrated the variant to have a significantly different EC50 (the concentration of ligand needed to achieve 50% of maximum effect) than that of the wild type (WT) receptor (Thearle_2012, Calton_2009), reduced expression at the cell surface and decreased receptor binding (Hohenadel_2014, Tan_2009) while, it also exhibited defective ligand-stimulated response compared to WT and was determined to have biased signaling in the ERK1/2 pathway (He_2014). Studies were contradictory in terms of cyclic AMP response after agonist administration either detecting loss of function or no significant difference in function compared to WT (Hohenadel_2014, Tan_2009). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the possibility that this is likely to represent a benign variation cannot be excluded. Due to equivocal reports of functional relevance the variant was classified as uncertain significance. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at