rs201533137
Positions:
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PVS1_StrongBP6BS2
The NM_002386.4(MC1R):c.67C>T(p.Gln23Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000251 in 1,612,270 control chromosomes in the GnomAD database, including 1 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 0.0013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00014 ( 1 hom. )
Consequence
MC1R
NM_002386.4 stop_gained
NM_002386.4 stop_gained
Scores
1
1
5
Clinical Significance
Conservation
PhyloP100: 0.0310
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 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 11 pathogenic variants in the truncated region.
BP6
?
Variant 16-89919325-C-T is Benign according to our data. Variant chr16-89919325-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 239159.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}.
BS2
?
High AC in GnomAd4 at 200 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MC1R | NM_002386.4 | c.67C>T | p.Gln23Ter | stop_gained | 1/1 | ENST00000555147.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MC1R | ENST00000555147.2 | c.67C>T | p.Gln23Ter | stop_gained | 1/1 | NM_002386.4 | P1 | ||
MC1R | ENST00000555427.1 | c.67C>T | p.Gln23Ter | stop_gained | 3/4 | 5 | |||
MC1R | ENST00000639847.1 | c.67C>T | p.Gln23Ter | stop_gained | 3/3 | 5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00132 AC: 201AN: 152196Hom.: 0 Cov.: 33
GnomAD3 genomes
?
AF:
AC:
201
AN:
152196
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000304 AC: 74AN: 243538Hom.: 1 AF XY: 0.000248 AC XY: 33AN XY: 133056
GnomAD3 exomes
AF:
AC:
74
AN:
243538
Hom.:
AF XY:
AC XY:
33
AN XY:
133056
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000140 AC: 204AN: 1459956Hom.: 1 Cov.: 30 AF XY: 0.000117 AC XY: 85AN XY: 726246
GnomAD4 exome
AF:
AC:
204
AN:
1459956
Hom.:
Cov.:
30
AF XY:
AC XY:
85
AN XY:
726246
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.00131 AC: 200AN: 152314Hom.: 0 Cov.: 33 AF XY: 0.00126 AC XY: 94AN XY: 74484
GnomAD4 genome
?
AF:
AC:
200
AN:
152314
Hom.:
Cov.:
33
AF XY:
AC XY:
94
AN XY:
74484
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ESP6500AA
AF:
AC:
11
ESP6500EA
AF:
AC:
0
ExAC
?
AF:
AC:
49
Asia WGS
AF:
AC:
3
AN:
3478
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 18, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 29, 2020 | Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 295 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Observed in one patient from a cohort of individuals at risk for pancreatic cancer, however, additional clinical details and family history were not provided (Smith er al., 2016); This variant is associated with the following publications: (PMID: 26546047, 12839583) - |
Melanoma, cutaneous malignant, susceptibility to, 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 05, 2024 | This sequence change creates a premature translational stop signal (p.Gln23*) in the MC1R gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 295 amino acid(s) of the MC1R protein. This variant is present in population databases (rs201533137, gnomAD 0.5%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with clinical features of MC1R-related conditions (PMID: 12839583). ClinVar contains an entry for this variant (Variation ID: 239159). 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
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
A;D
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at