rs780875127
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PVS1_StrongBS2
The NM_002386.4(MC1R):c.496dup(p.Ala166GlyfsTer73) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000162 in 1,608,252 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
MC1R
NM_002386.4 frameshift
NM_002386.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.38
Genes affected
MC1R (HGNC:6929): (melanocortin 1 receptor) This intronless gene encodes the receptor protein for melanocyte-stimulating hormone (MSH). The encoded protein, a seven pass transmembrane G protein coupled receptor, controls melanogenesis. Two types of melanin exist: red pheomelanin and black eumelanin. Gene mutations that lead to a loss in function are associated with increased pheomelanin production, which leads to lighter skin and hair color. Eumelanin is photoprotective but pheomelanin may contribute to UV-induced skin damage by generating free radicals upon UV radiation. Binding of MSH to its receptor activates the receptor and stimulates eumelanin synthesis. This receptor is a major determining factor in sun sensitivity and is a genetic risk factor for melanoma and non-melanoma skin cancer. Over 30 variant alleles have been identified which correlate with skin and hair color, providing evidence that this gene is an important component in determining normal human pigment variation. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.481 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
BS2
High AC in GnomAdExome4 at 23 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MC1R | NM_002386.4 | c.496dup | p.Ala166GlyfsTer73 | frameshift_variant | 1/1 | ENST00000555147.2 | NP_002377.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MC1R | ENST00000555147.2 | c.496dup | p.Ala166GlyfsTer73 | frameshift_variant | 1/1 | NM_002386.4 | ENSP00000451605 | P1 | ||
MC1R | ENST00000555427.1 | c.496dup | p.Ala166GlyfsTer73 | frameshift_variant | 3/4 | 5 | ENSP00000451760 | |||
MC1R | ENST00000639847.1 | c.496dup | p.Ala166GlyfsTer73 | frameshift_variant | 3/3 | 5 | ENSP00000492011 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152226Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000122 AC: 3AN: 245254Hom.: 0 AF XY: 0.00000749 AC XY: 1AN XY: 133542
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GnomAD4 exome AF: 0.0000158 AC: 23AN: 1456026Hom.: 0 Cov.: 35 AF XY: 0.0000179 AC XY: 13AN XY: 724586
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152226Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74360
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Melanoma, cutaneous malignant, susceptibility to, 5 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Dec 18, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The MC1R c.496dupG (p.Ala166GlyfsTer73) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Ala166GlyfsTer73 variant has been reported in one study in which it is found in one individual with sporadic malignant melanoma in a heterozygous state (Galore-Haskel et al. 2009). This variant was absent from controls, but is reported at a frequency of 0.00012 in the European American population of the Exome Sequencing Project, however this is based on one allele in a region of good sequence coverage so the variant is presumed to be rare. Due to the potential impact of frameshift variants, and the limited evidence in the literature, the p.Ala166GlyfsTer73 variant is classified as a variant of unknown significance, but is suspicious for pathogenicity for malignant melanoma susceptibility. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 09, 2022 | This sequence change creates a premature translational stop signal (p.Ala166Glyfs*73) in the MC1R gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 152 amino acid(s) of the MC1R protein. This variant is present in population databases (rs780875127, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with malignant melanoma (PMID: 19269164). ClinVar contains an entry for this variant (Variation ID: 321429). 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
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at