rs1805008

chr16-89919736-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R160Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.046 (207 hom., cov: 33)
  • Exomes 𝑓: 0.071 (4361 hom.)
• Consequence: MC1R NM_002386.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:5 O:3
• 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]

ACMG classification

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	UniProt
MC1R	NM_002386.4	c.478C>T	p.Arg160Trp	missense_variant	1/1	ENST00000555147.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MC1R	ENST00000555147.2	c.478C>T	p.Arg160Trp	missense_variant	1/1		NM_002386.4	P1
MC1R	ENST00000555427.1	c.478C>T	p.Arg160Trp	missense_variant	3/4	5
MC1R	ENST00000639847.1	c.478C>T	p.Arg160Trp	missense_variant	3/3	5		P1

Frequencies

GnomAD3 genomes AF: 0.0463 AC: 7051 AN: 152244 Hom.: 207 Cov.: 33

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.0135

Gnomad ASJ AF: 0.0599

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.0610

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0772

Gnomad OTH AF: 0.0287

GnomAD3 exomes AF: 0.0472 AC: 11354 AN: 240724 Hom.: 446 AF XY: 0.0467 AC XY: 6152 AN XY: 131798

Gnomad AFR exome AF: 0.0129

Gnomad AMR exome AF: 0.00819

Gnomad ASJ exome AF: 0.0579

Gnomad EAS exome AF: 0.0000558

Gnomad SAS exome AF: 0.00524

Gnomad FIN exome AF: 0.0643

Gnomad NFE exome AF: 0.0800

Gnomad OTH exome AF: 0.0427

GnomAD4 exome AF: 0.0708 AC: 102907 AN: 1453706 Hom.: 4361 Cov.: 36 AF XY: 0.0687 AC XY: 49732 AN XY: 723538

Gnomad4 AFR exome AF: 0.0106

Gnomad4 AMR exome AF: 0.00830

Gnomad4 ASJ exome AF: 0.0563

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00611

Gnomad4 FIN exome AF: 0.0661

Gnomad4 NFE exome AF: 0.0843

Gnomad4 OTH exome AF: 0.0546

GnomAD4 genome AF: 0.0463 AC: 7052 AN: 152362 Hom.: 207 Cov.: 33 AF XY: 0.0439 AC XY: 3270 AN XY: 74498

Gnomad4 AFR AF: 0.0133

Gnomad4 AMR AF: 0.0135

Gnomad4 ASJ AF: 0.0599

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.0610

Gnomad4 NFE AF: 0.0772

Gnomad4 OTH AF: 0.0284

Alfa AF: 0.0625 Hom.: 512

Bravo AF: 0.0412

TwinsUK AF: 0.0890 AC: 330

ALSPAC AF: 0.0926 AC: 357

ESP6500AA AF: 0.0135 AC: 59

ESP6500EA AF: 0.0771 AC: 663

ExAC AF: 0.0497 AC: 6022

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.0628

EpiControl AF: 0.0681

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:5 Other:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1 Benign:1

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 -
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. -

Melanoma, cutaneous malignant, susceptibility to, 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	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

- -

OCULOCUTANEOUS ALBINISM, TYPE II, MODIFIER OF Other:1

risk factor, 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	0.050
Cadd	Benign	18
Dann	Uncertain	1.0
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.91	D;.;D;D
MetaRNN	Benign	0.0057	T;T;T;T
MetaSVM	Benign	-0.62	T
MutationTaster	Benign	0.99	D;D
PROVEAN	Pathogenic	-7.0	D;.;D;N
REVEL	Benign	0.27
Sift	Uncertain	0.010	D;.;D;D
Sift4G	Pathogenic	0.0010	D;.;D;D
Polyphen		0.86	.;P;P;.
Vest4		0.94
MPC		0.067
ClinPred		1.0	D
GERP RS		0.042
Varity_R		0.36
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1805008; hg19: chr16-89986144; COSMIC: COSV59625425; COSMIC: COSV59625425;