rs143395134
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5
The NM_002386.4(MC1R):āc.894C>Gā(p.Tyr298Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).
Frequency
Genomes: not found (cov: 33)
Exomes š: 0.0000027 ( 0 hom. )
Consequence
MC1R
NM_002386.4 stop_gained
NM_002386.4 stop_gained
Scores
2
1
4
Clinical Significance
Conservation
PhyloP100: -2.81
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 5 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 0.0629 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-89920152-C-G is Pathogenic according to our data. Variant chr16-89920152-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 548661.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MC1R | NM_002386.4 | c.894C>G | p.Tyr298Ter | stop_gained | 1/1 | ENST00000555147.2 | NP_002377.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MC1R | ENST00000555147.2 | c.894C>G | p.Tyr298Ter | stop_gained | 1/1 | NM_002386.4 | ENSP00000451605 | P1 | ||
ENST00000554623.1 | n.660G>C | non_coding_transcript_exon_variant | 2/2 | 3 | ||||||
MC1R | ENST00000555427.1 | c.894C>G | p.Tyr298Ter | stop_gained | 3/4 | 5 | ENSP00000451760 | |||
MC1R | ENST00000639847.1 | c.894C>G | p.Tyr298Ter | stop_gained | 3/3 | 5 | ENSP00000492011 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
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33
GnomAD3 exomes AF: 0.00000803 AC: 2AN: 249030Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135190
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461678Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3AN XY: 727122
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GnomAD4 genome Cov.: 33
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Tyrosinase-positive oculocutaneous albinism Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Sep 22, 2015 | - - |
Skin and Hair Hypopigmentation Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | Sep 22, 2015 | - - |
Computational scores
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Name
Calibrated prediction
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Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
A;D
Vest4
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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