NM_002386.4:c.464T>C
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_002386.4(MC1R):c.464T>C(p.Ile155Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0094 in 1,606,272 control chromosomes in the GnomAD database, including 102 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_002386.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MC1R | ENST00000555147.2 | c.464T>C | p.Ile155Thr | missense_variant | Exon 1 of 1 | 6 | NM_002386.4 | ENSP00000451605.1 | ||
ENSG00000198211 | ENST00000556922.1 | c.464T>C | p.Ile155Thr | missense_variant | Exon 1 of 5 | 2 | ENSP00000451560.1 | |||
MC1R | ENST00000555427.1 | c.464T>C | p.Ile155Thr | missense_variant | Exon 3 of 4 | 5 | ENSP00000451760.1 | |||
MC1R | ENST00000639847.1 | c.464T>C | p.Ile155Thr | missense_variant | Exon 3 of 3 | 5 | ENSP00000492011.1 |
Frequencies
GnomAD3 genomes AF: 0.00661 AC: 1007AN: 152244Hom.: 3 Cov.: 33
GnomAD3 exomes AF: 0.00564 AC: 1366AN: 242204Hom.: 1 AF XY: 0.00564 AC XY: 745AN XY: 132048
GnomAD4 exome AF: 0.00969 AC: 14089AN: 1453910Hom.: 99 Cov.: 34 AF XY: 0.00935 AC XY: 6764AN XY: 723646
GnomAD4 genome AF: 0.00662 AC: 1008AN: 152362Hom.: 3 Cov.: 33 AF XY: 0.00553 AC XY: 412AN XY: 74504
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:2Benign:1
The I155T variant in the MC1R gene has been reported numerous times in the both the heterozygous and homozygous states in association with MC1R-related phenotypes including red hair, changes in skin pigmentation, and an increased risk for UV exposure-related melanoma (Flanagan et al., 2000; Beaumont et al., 2007; Raimondi et al., 2008; Cust et al., 2012; Puig-Butillé et al., 2013). The NHLBI Exome Sequencing Project reports I155T was observed in 1.05% (90/8598) alleles from individuals of European American ancestry. The I155T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. Functional studies demonstrate that I155T reduces cell surface expression of the MC1R protein and results in loss of cAMP signaling (Beaumont et al., 2007). -
MC1R: BP4, BS1, BS2 -
The MC1R c.464T>C; p.Ile155Thr variant (rs1110400) is reported in the literature in individuals affected with melanoma (Aviles 2012, Bassoli 2013, Hatvani 2014, Puig-Butille 2013). However, several studies found only a slightly increased association with melanoma, with odds ratios of 1.14-2.45 (Morgan 2018, Raimondi 2008, Williams 2011). This variant is also reported in ClinVar (Variation ID: 239154), and is found in the general population with an overall allele frequency of 0.57% (1566/273582 alleles, including a single homozygote) in the Genome Aggregation Database. The isoleucine at codon 155 is highly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.234). In vitro functional analyses demonstrate decreased cell surface expression of the MC1R protein and reduced cAMP signaling (Beaumont 2007). Based on available information, it is uncertain whether this variant increases the risk for melanoma. References: Aviles JA et al. Phenotypic and histologic characteristics of cutaneous melanoma in patients with melanocortin-1 receptor polymorphisms. Actas Dermosifiliogr. 2012 Jan;103(1):44-50. PMID: 22464597. Bassoli S et al. CDKN2A and MC1R variants influence dermoscopic and confocal features of benign melanocytic lesions in multiple melanoma patients. Exp Dermatol. 2013 Jun;22(6):411-6. PMID: 23711066. Beaumont KA et al. Receptor function, dominant negative activity and phenotype correlations for MC1R variant alleles. Hum Mol Genet. 2007 Sep 15;16(18):2249-60. PMID: 17616515. Hatvani Z et al. Genotype analysis in Hungarian patients with multiple primary melanoma. Exp Dermatol. 2014 May;23(5):361-4. PMID: 24660985. Morgan MD et al. Genome-wide study of hair colour in UK Biobank explains most of the SNP heritability. Nat Commun. 2018 Dec 10;9(1):5271. PMID: 30531825. Puig-Butille JA et al. Distribution of MC1R variants among melanoma subtypes: p.R163Q is associated with lentigo maligna melanoma in a Mediterranean population. Br J Dermatol. 2013 Oct;169(4):804-11. PMID: 23647022. Raimondi S et al. MC1R variants, melanoma and red hair color phenotype: a meta-analysis. Int J Cancer. 2008 Jun 15;122(12):2753-60. PMID: 18366057. Williams PF et al. Melanocortin 1 receptor and risk of cutaneous melanoma: a meta-analysis and estimates of population burden. Int J Cancer. 2011 Oct 1;129(7):1730-40. PMID: 21128237. -
The MC1R p.Ile155Thr variant was reported in the literature with an association to red hair colour, fair skin colour, and melanoma risk phenotypes (Morgan_2018_PMID:30531825; Liu_2015_PMID:25963972; Williams_2011_PMID:21128237; Raimondi_2008_PMID:18366057). The variant was identified in dbSNP (ID: rs1110400), ClinVar (classified as benign 1x, likely benign 2x, pathogenic 1x by GeneDx, and uncertain significance 1x), and LOVD 3.0, however it was not identified in Cosmic. The variant was identified in control databases in 1566 of 273582 chromosomes (1 homozygous) at a frequency of 0.005724 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 1180 of 126992 chromosomes (freq: 0.009292), Ashkenazi Jewish in 88 of 10294 chromosomes (freq: 0.008549), Other in 45 of 7096 chromosomes (freq: 0.006342), Latino in 148 of 35326 chromosomes (freq: 0.00419), African in 55 of 24388 chromosomes (freq: 0.002255), European (Finnish) in 36 of 19442 chromosomes (freq: 0.001852) and South Asian in 14 of 30564 chromosomes (freq: 0.000458); it was not observed in the East Asian population. One functional study showed I155T G-protein coupled receptors, which are expressed on melanocytes and play a role in pigmentation regulation, displayed an 85% decrease in plasma membrane receptor levels (Beaumont_2005_PMID:15972726). Although the p.Ile155 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, BLOSUM, MutationTaster) suggest that the variant may impact the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
not specified Benign:2
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Variant summary: MC1R c.464T>C (p.Ile155Thr) results in a non-conservative amino acid change located in the G-protein coupled receptors family 1 profile (IPR017452) 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 0.0056 in 242204 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency exceeds the estimated maximal expected allele frequency for a pathogenic variant in MC1R causing MC1R-Related Disorders phenotype. c.464T>C has been reported in the literature in individuals affected with MC1R-Related Disorders and melanoma (Flanagan_2000, Puig-Butill_2012, Avils_2012). These report(s) do not provide unequivocal conclusions about association of the variant with MC1R-Related Disorders. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity in an in vitro cellular assay (Beaumont_2007). The following publications have been ascertained in the context of this evaluation (PMID: 22464597, 17616515, 11030758, 34326492, 23647022). ClinVar contains an entry for this variant (Variation ID: 239154). Based on the evidence outlined above, the variant was classified as likely benign. -
Melanoma, cutaneous malignant, susceptibility to, 5 Benign:2
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
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Tyrosinase-positive oculocutaneous albinism;C1849452:Skin/hair/eye pigmentation, variation in, 2;C2751295:Melanoma, cutaneous malignant, susceptibility to, 5;C2751296:Increased analgesia from kappa-opioid receptor agonist, female-specific Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at