16-89919722-T-C

Position:

• chr16-89919722-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002386.4(MC1R):​c.464T>C​(p.Ile155Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0094 in 1,606,272 control chromosomes in the GnomAD database, including 102 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0066 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0097 (99 hom.)
• Consequence: MC1R NM_002386.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:4
• Conservation: PhyloP100: 5.05

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0065425932).
• BS2: High AC in GnomAd4 at 1008 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MC1R	NM_002386.4	c.464T>C	p.Ile155Thr	missense_variant	1/1	ENST00000555147.2	NP_002377.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MC1R	ENST00000555147.2	c.464T>C	p.Ile155Thr	missense_variant	1/1		NM_002386.4	ENSP00000451605	P1
MC1R	ENST00000555427.1	c.464T>C	p.Ile155Thr	missense_variant	3/4	5		ENSP00000451760
MC1R	ENST00000639847.1	c.464T>C	p.Ile155Thr	missense_variant	3/3	5		ENSP00000492011	P1

Frequencies

GnomAD3 genomes AF: 0.00661 AC: 1007 AN: 152244 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00719

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.00564 AC: 1366 AN: 242204 Hom.: 1 AF XY: 0.00564 AC XY: 745 AN XY: 132048

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00409

Gnomad ASJ exome AF: 0.00860

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000458

Gnomad FIN exome AF: 0.00188

Gnomad NFE exome AF: 0.00922

Gnomad OTH exome AF: 0.00616

GnomAD4 exome AF: 0.00969 AC: 14089 AN: 1453910 Hom.: 99 Cov.: 34 AF XY: 0.00935 AC XY: 6764 AN XY: 723646

Gnomad4 AFR exome AF: 0.00161

Gnomad4 AMR exome AF: 0.00445

Gnomad4 ASJ exome AF: 0.00846

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000441

Gnomad4 FIN exome AF: 0.00253

Gnomad4 NFE exome AF: 0.0116

Gnomad4 OTH exome AF: 0.00978

GnomAD4 genome AF: 0.00662 AC: 1008 AN: 152362 Hom.: 3 Cov.: 33 AF XY: 0.00553 AC XY: 412 AN XY: 74504

Gnomad4 AFR AF: 0.00231

Gnomad4 AMR AF: 0.00718

Gnomad4 ASJ AF: 0.0107

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000827

Gnomad4 FIN AF: 0.00235

Gnomad4 NFE AF: 0.0106

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00905 Hom.: 5

Bravo AF: 0.00638

TwinsUK AF: 0.00944 AC: 35

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00296 AC: 13

ESP6500EA AF: 0.0105 AC: 90

ExAC AF: 0.00523 AC: 635

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0101

EpiControl AF: 0.00883

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:2 Benign:1

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	MC1R: BP4, BS1, BS2 -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MC1R p.Ile155Thr variant was reported in the literature with an association to red hair colour, fair skin colour, and melanoma risk phenotypes (Morgan_2018_PMID:30531825; Liu_2015_PMID:25963972; Williams_2011_PMID:21128237; Raimondi_2008_PMID:18366057). The variant was identified in dbSNP (ID: rs1110400), ClinVar (classified as benign 1x, likely benign 2x, pathogenic 1x by GeneDx, and uncertain significance 1x), and LOVD 3.0, however it was not identified in Cosmic. The variant was identified in control databases in 1566 of 273582 chromosomes (1 homozygous) at a frequency of 0.005724 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 1180 of 126992 chromosomes (freq: 0.009292), Ashkenazi Jewish in 88 of 10294 chromosomes (freq: 0.008549), Other in 45 of 7096 chromosomes (freq: 0.006342), Latino in 148 of 35326 chromosomes (freq: 0.00419), African in 55 of 24388 chromosomes (freq: 0.002255), European (Finnish) in 36 of 19442 chromosomes (freq: 0.001852) and South Asian in 14 of 30564 chromosomes (freq: 0.000458); it was not observed in the East Asian population. One functional study showed I155T G-protein coupled receptors, which are expressed on melanocytes and play a role in pigmentation regulation, displayed an 85% decrease in plasma membrane receptor levels (Beaumont_2005_PMID:15972726). Although the p.Ile155 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, BLOSUM, MutationTaster) suggest that the variant may impact the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2023	The MC1R c.464T>C; p.Ile155Thr variant (rs1110400) is reported in the literature in individuals affected with melanoma (Aviles 2012, Bassoli 2013, Hatvani 2014, Puig-Butille 2013). However, several studies found only a slightly increased association with melanoma, with odds ratios of 1.14-2.45 (Morgan 2018, Raimondi 2008, Williams 2011). This variant is also reported in ClinVar (Variation ID: 239154), and is found in the general population with an overall allele frequency of 0.57% (1566/273582 alleles, including a single homozygote) in the Genome Aggregation Database. The isoleucine at codon 155 is highly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.234). In vitro functional analyses demonstrate decreased cell surface expression of the MC1R protein and reduced cAMP signaling (Beaumont 2007). Based on available information, it is uncertain whether this variant increases the risk for melanoma. References: Aviles JA et al. Phenotypic and histologic characteristics of cutaneous melanoma in patients with melanocortin-1 receptor polymorphisms. Actas Dermosifiliogr. 2012 Jan;103(1):44-50. PMID: 22464597. Bassoli S et al. CDKN2A and MC1R variants influence dermoscopic and confocal features of benign melanocytic lesions in multiple melanoma patients. Exp Dermatol. 2013 Jun;22(6):411-6. PMID: 23711066. Beaumont KA et al. Receptor function, dominant negative activity and phenotype correlations for MC1R variant alleles. Hum Mol Genet. 2007 Sep 15;16(18):2249-60. PMID: 17616515. Hatvani Z et al. Genotype analysis in Hungarian patients with multiple primary melanoma. Exp Dermatol. 2014 May;23(5):361-4. PMID: 24660985. Morgan MD et al. Genome-wide study of hair colour in UK Biobank explains most of the SNP heritability. Nat Commun. 2018 Dec 10;9(1):5271. PMID: 30531825. Puig-Butille JA et al. Distribution of MC1R variants among melanoma subtypes: p.R163Q is associated with lentigo maligna melanoma in a Mediterranean population. Br J Dermatol. 2013 Oct;169(4):804-11. PMID: 23647022. Raimondi S et al. MC1R variants, melanoma and red hair color phenotype: a meta-analysis. Int J Cancer. 2008 Jun 15;122(12):2753-60. PMID: 18366057. Williams PF et al. Melanocortin 1 receptor and risk of cutaneous melanoma: a meta-analysis and estimates of population burden. Int J Cancer. 2011 Oct 1;129(7):1730-40. PMID: 21128237. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 01, 2016	The I155T variant in the MC1R gene has been reported numerous times in the both the heterozygous and homozygous states in association with MC1R-related phenotypes including red hair, changes in skin pigmentation, and an increased risk for UV exposure-related melanoma (Flanagan et al., 2000; Beaumont et al., 2007; Raimondi et al., 2008; Cust et al., 2012; Puig-Butillé et al., 2013). The NHLBI Exome Sequencing Project reports I155T was observed in 1.05% (90/8598) alleles from individuals of European American ancestry. The I155T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. Functional studies demonstrate that I155T reduces cell surface expression of the MC1R protein and results in loss of cAMP signaling (Beaumont et al., 2007). -

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	.;T;T;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.78	T;.;T;T
MetaRNN	Benign	0.0065	T;T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Pathogenic	3.2	.;M;M;.
MutationTaster	Benign	1.0	D;D
PROVEAN	Pathogenic	-4.6	D;.;D;N
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Pathogenic	0.0	D;.;D;D
Polyphen		0.99	.;D;D;.
Vest4		0.71
MVP		0.74
MPC		0.10
ClinPred		0.054	T
GERP RS		4.8
Varity_R		0.78
gMVP		0.38

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: rs1110400; hg19: chr16-89986130;