rs201326893
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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.456C>A(p.Tyr152Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00054 in 1,606,408 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00054 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00054 ( 5 hom. )
Consequence
MC1R
NM_002386.4 stop_gained
NM_002386.4 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 1.38
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. There are 4 pathogenic variants in the truncated region.
BS2
?
High AC in GnomAd4 at 83 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MC1R | NM_002386.4 | c.456C>A | p.Tyr152Ter | stop_gained | 1/1 | ENST00000555147.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MC1R | ENST00000555147.2 | c.456C>A | p.Tyr152Ter | stop_gained | 1/1 | NM_002386.4 | P1 | ||
MC1R | ENST00000555427.1 | c.456C>A | p.Tyr152Ter | stop_gained | 3/4 | 5 | |||
MC1R | ENST00000639847.1 | c.456C>A | p.Tyr152Ter | stop_gained | 3/3 | 5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000545 AC: 83AN: 152264Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000840 AC: 204AN: 242812Hom.: 2 AF XY: 0.000870 AC XY: 115AN XY: 132240
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GnomAD4 exome AF: 0.000539 AC: 784AN: 1454026Hom.: 5 Cov.: 34 AF XY: 0.000547 AC XY: 396AN XY: 723708
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GnomAD4 genome ? AF: 0.000545 AC: 83AN: 152382Hom.: 0 Cov.: 33 AF XY: 0.000564 AC XY: 42AN XY: 74512
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Melanoma, cutaneous malignant, susceptibility to, 5 Uncertain:1Benign:1
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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change creates a premature translational stop signal (p.Tyr152*) in the MC1R gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 166 amino acid(s) of the MC1R protein. This variant is present in population databases (rs201326893, gnomAD 1.0%), and has an allele count higher than expected for a pathogenic variant. This variant has been reported in individuals affected with melanoma (PMID: 23522749, 15998953, 19269164, 17496785, 31382929), as well as unaffected individuals (PMID: 15221796, 19585506, 19269164). lt has been observed more frequently in individuals with red hair and pale skin phenotypes (PMID: 11933208, 17316231). Pigmentation of the hair and skin is correlated with ultraviolet sensitivity and skin cancer. Other loss-of-function missense variants in MC1R have been correlated with lighter skin pigmentation (PMID: 11030758) and possibly increased melanoma risk, although no definitive disease association has been concluded (PMID: 18366057, 21128237). ClinVar contains an entry for this variant (Variation ID: 265230). 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 28, 2018 | Nonsense variant predicted to result in protein truncation in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; This variant is associated with the following publications: (PMID: 11933208, 34662886, 16567973, 15998953, 30531825, 31382929, 26689913, 34426522, 23711066, 17496785) - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;D
Vest4
GERP RS
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