rs753749977
Positions:
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_002386.4(MC1R):āc.860T>Gā(p.Ile287Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000465 in 1,613,842 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I287M) has been classified as Likely benign.
Frequency
Genomes: š 0.000046 ( 0 hom., cov: 33)
Exomes š: 0.000047 ( 0 hom. )
Consequence
MC1R
NM_002386.4 missense
NM_002386.4 missense
Scores
5
8
3
Clinical Significance
Conservation
PhyloP100: 6.19
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 Likely_benign. Variant got -4 ACMG points.
BS2
?
High AC in GnomAd4 at 7 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MC1R | NM_002386.4 | c.860T>G | p.Ile287Ser | missense_variant | 1/1 | ENST00000555147.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MC1R | ENST00000555147.2 | c.860T>G | p.Ile287Ser | missense_variant | 1/1 | NM_002386.4 | P1 | ||
ENST00000554623.1 | n.694A>C | non_coding_transcript_exon_variant | 2/2 | 3 | |||||
MC1R | ENST00000555427.1 | c.860T>G | p.Ile287Ser | missense_variant | 3/4 | 5 | |||
MC1R | ENST00000639847.1 | c.860T>G | p.Ile287Ser | missense_variant | 3/3 | 5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152194Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000161 AC: 4AN: 249168Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135214
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GnomAD4 exome AF: 0.0000465 AC: 68AN: 1461648Hom.: 0 Cov.: 35 AF XY: 0.0000399 AC XY: 29AN XY: 727104
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GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152194Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74348
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Melanoma, cutaneous malignant, susceptibility to, 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 17, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 287 of the MC1R protein (p.Ile287Ser). This variant is present in population databases (rs753749977, gnomAD 0.005%). This missense change has been observed in individual(s) with melanoma (PMID: 16982779). ClinVar contains an entry for this variant (Variation ID: 406216). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MC1R protein function. 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
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;.;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PROVEAN
Pathogenic
D;.;D;N
REVEL
Uncertain
Sift
Pathogenic
D;.;D;D
Sift4G
Pathogenic
D;.;D;D
Polyphen
1.0
.;D;D;.
Vest4
MutPred
Loss of stability (P = 0.0143);Loss of stability (P = 0.0143);Loss of stability (P = 0.0143);Loss of stability (P = 0.0143);
MVP
MPC
0.13
ClinPred
D
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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