rs1805008
Positions:
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1
The NM_002386.4(MC1R):c.478C>T(p.Arg160Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0685 in 1,606,068 control chromosomes in the GnomAD database, including 4,568 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
Genomes: 𝑓 0.046 ( 207 hom., cov: 33)
Exomes 𝑓: 0.071 ( 4361 hom. )
Consequence
MC1R
NM_002386.4 missense
NM_002386.4 missense
Scores
3
5
9
Clinical Significance
Conservation
PhyloP100: 1.23
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 Benign. Variant got -12 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.0057244897).
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0754 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MC1R | NM_002386.4 | c.478C>T | p.Arg160Trp | missense_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.478C>T | p.Arg160Trp | missense_variant | 1/1 | NM_002386.4 | ENSP00000451605 | P1 | ||
MC1R | ENST00000555427.1 | c.478C>T | p.Arg160Trp | missense_variant | 3/4 | 5 | ENSP00000451760 | |||
MC1R | ENST00000639847.1 | c.478C>T | p.Arg160Trp | missense_variant | 3/3 | 5 | ENSP00000492011 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0463 AC: 7051AN: 152244Hom.: 207 Cov.: 33
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GnomAD3 exomes AF: 0.0472 AC: 11354AN: 240724Hom.: 446 AF XY: 0.0467 AC XY: 6152AN XY: 131798
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GnomAD4 exome AF: 0.0708 AC: 102907AN: 1453706Hom.: 4361 Cov.: 36 AF XY: 0.0687 AC XY: 49732AN XY: 723538
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GnomAD4 genome AF: 0.0463 AC: 7052AN: 152362Hom.: 207 Cov.: 33 AF XY: 0.0439 AC XY: 3270AN XY: 74498
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1Benign:5Other:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:1Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MC1R p.Arg160Trp variant was identified in dbSNP (ID: rs1805008) as “With Pathogenic allele” and in ClinVar as conflicting interpretations of pathogenicity (six submissions: likely benign by PreventionGenetics and Illumina Clinical Services Laboratory, pathogenic by GeneDx, and three submissions from OMIM). The associated conditions in ClinVar include: increased analgesia from kappa-opioid receptor agonist, female-specific; skin/hair/eye pigmentation 2, red hair/fair skin; modifier of oculocutaneous albinism, type II; and malignant melanoma susceptibility. The variant was also in Clinvitae and LOVD 3.0 databases. The variant was not identified in COGR, Cosmic, MutDB, and UMD-LSDB databases. The variant was identified in control databases in 12963 of 272086 chromosomes (487 homozygous) at a frequency of 0.047643 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 10040 of 126010 chromosomes (freq: 0.07968), European (Finnish) in 1282 of 19538 chromosomes (freq: 0.06562), Ashkenazi Jewish in 589 of 10256 chromosomes (freq: 0.05743), Other in 298 of 7034 chromosomes (freq: 0.04237), African in 304 of 23942 chromosomes (freq: 0.0127), Latino in 289 of 35298 chromosomes (freq: 0.008187), South Asian in 160 of 30534 chromosomes (freq: 0.00524), and East Asian in 1 of 19474 chromosomes (freq: 0.000051). Raimondi et al. performed a meta-analysis on the association between the most studied MC1R variants, including p.Arg160Trp, and melanoma and/or red hair, fair skin phenotype. The variant was significantly associated with melanoma development, with OR of 1.43 (95 CI) and with red hair and fair skin with OR of 5.0 (95% CI) (Raimondi_2008_18366057). Tagliabue et al. investigated the association between MC1R variants and the risk of non-melanoma skin cancer (NMSC). Data on 3257 NMSC cases and 9391 controls was gathered through the M-SKIP Project (an international pooled-analysis on MC1R, skin cancer and phenotypic characteristics). The variant p.Arg160Trp showed a positive association with NMSC with a summary odds ratio of 1.67 (Tagliabue_2015_26103569). The p.Arg160 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The p.Arg160 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. References: Raimondi, Sara, et al. "MC1R variants, melanoma and red hair color phenotype: a meta‐analysis." International Journal of Cancer 122.12 (2008): 2753-2760. Tagliabue, Elena, et al. "MC1R gene variants and non-melanoma skin cancer: a pooled-analysis from the M-SKIP project." British journal of cancer 113.2 (2015): 354. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 07, 2016 | The R160W variant in the MC1R gene has been reported numerous times in the homozygous and compound heterozygous state in association with MC1R-related phenotypes including red hair, changes in skin pigmentation, and an increased risk for UV exposure-related melanoma (Smith et al., 1998; Raimondi et al., 2008; Szell et al., 2008; Hoiom et al., 2009). The NHLBI ESP Exome Sequencing Project reports R160W was observed in 7.7% (663/8594) alleles from individuals of European American background. The R160W variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. Functional studies have shown that the R160W variant reduces cell surface expression of the MC1R protein and results in loss of cAMP signalling (Beaumont et al., 2007; Sanchez-Laorden et al., 2009). We interpret R160W as a risk allele associated with an increased risk for UV exposure-related melanoma. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 23, 2023 | PS3_supporting, PS4_moderate - |
Melanoma, cutaneous malignant, susceptibility to, 5 Benign:2
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Malignant tumor of breast Benign:1
Likely benign, no assertion criteria provided | clinical testing | Center of Medical Genetics and Primary Health Care | - | - - |
Skin/hair/eye pigmentation 2, red hair/fair skin Other:1
association, no assertion criteria provided | literature only | OMIM | May 01, 2015 | - - |
Increased analgesia from kappa-opioid receptor agonist, female-specific Other:1
Affects, no assertion criteria provided | literature only | OMIM | May 01, 2015 | - - |
ALBINISM, OCULOCUTANEOUS, TYPE II, MODIFIER OF Other:1
risk factor, no assertion criteria provided | literature only | OMIM | May 01, 2015 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
.;T;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;.;D;D
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Pathogenic
.;H;H;.
MutationTaster
Benign
D;D
PROVEAN
Pathogenic
D;.;D;N
REVEL
Benign
Sift
Uncertain
D;.;D;D
Sift4G
Pathogenic
D;.;D;D
Polyphen
0.86
.;P;P;.
Vest4
MPC
0.067
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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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