chr18-60371440-G-A
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM1BP4_ModerateBS2_Supporting
The NM_005912.3(MC4R):c.910C>T(p.Leu304Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,614,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (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.910C>T | p.Leu304Phe | missense_variant | Exon 1 of 1 | 6 | NM_005912.3 | ENSP00000299766.3 | ||
ENSG00000285681 | ENST00000650201.1 | n.113+42095G>A | intron_variant | Intron 1 of 3 | ||||||
ENSG00000285681 | ENST00000658928.1 | n.156+42095G>A | intron_variant | Intron 1 of 3 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152208Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000477 AC: 12AN: 251410Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135874
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461830Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 727222
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152208Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74362
ClinVar
Submissions by phenotype
MC4R-related disorder Uncertain:1
The MC4R c.910C>T variant is predicted to result in the amino acid substitution p.Leu304Phe. This variant has been reported in the heterozygous state in individuals with obesity (van den Berg et al. 2011. PubMed ID: 20966905; Thearle et al. 2011. PubMed ID: 22106157). Functional studies analyzing NDP-MSH receptor binding in HEK cells showed that this variant decreased expression levels to ~40% of wild receptor expression and cell surface expression and retainment in the ER was decreased as compared to wildtype (van den Berg et al. 2011. PubMed ID: 20966905); however another study showed p.Leu304Phe had no impact on MC4R function (Thearle et al. 2011. PubMed ID: 22106157). In addition, affinity for NDP-MSH and receptor activation was not significantly altered as compared to wildtype (van den Berg et al. 2011. PubMed ID: 20966905). Another study analyzing signaling preference for gain-of-function MC4R variants determined that the p.Leu304Phe variant had no evidence of biased signaling (Lotta et al. 2019. PubMed ID: 31002796). This variant is reported in 0.034% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant 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