NM_005912.3:c.914G>A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PP3_ModerateBS2
The NM_005912.3(MC4R):c.914G>A(p.Arg305Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,613,936 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_005912.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MC4R | ENST00000299766.5 | c.914G>A | p.Arg305Gln | missense_variant | Exon 1 of 1 | 6 | NM_005912.3 | ENSP00000299766.3 | ||
ENSG00000285681 | ENST00000650201.1 | n.113+42091C>T | intron_variant | Intron 1 of 3 | ||||||
ENSG00000285681 | ENST00000658928.1 | n.156+42091C>T | intron_variant | Intron 1 of 3 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152118Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251408Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135874
GnomAD4 exome AF: 0.0000219 AC: 32AN: 1461818Hom.: 1 Cov.: 31 AF XY: 0.0000220 AC XY: 16AN XY: 727226
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152118Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74292
ClinVar
Submissions by phenotype
BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20 Uncertain:1
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Obesity Uncertain:1
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MC4R-related disorder Uncertain:1
The MC4R c.914G>A variant is predicted to result in the amino acid substitution p.Arg305Gln. This variant was reported in three individuals with obesity (Reinehr et al. 2009. PubMed ID: 18997677; Moore et al. 2014. PubMed ID: 24705671). This variant was also reported in one control individual in a case-control study (Calton et al. 2009. PubMed ID: 19091795). Functional studies suggest that this variant led to reduced gene function (Reinehr et al. 2009. PubMed ID: 18997677; Calton et al. 2009. PubMed ID: 19091795; He and Tao. 2014. PubMed ID: 25332687) and reduced cell surface expression (Moore et al. 2014. PubMed ID: 24705671). This variant is reported in 0.022% of alleles in individuals of East Asian descent in gnomAD. Although we suspect this variant may be pathogenic, at this time, the clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at