rs200050206

chr16-89919370-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002386.4(MC1R):c.112G>A(p.Val38Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,613,188 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (3 hom.)
• Consequence: MC1R NM_002386.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.808

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14184731).
• BS2: High AC in GnomAd at 57 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MC1R	NM_002386.4	c.112G>A	p.Val38Met	missense_variant	1/1	ENST00000555147.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MC1R	ENST00000555147.2	c.112G>A	p.Val38Met	missense_variant	1/1		NM_002386.4	P1
MC1R	ENST00000555427.1	c.112G>A	p.Val38Met	missense_variant	3/4	5
MC1R	ENST00000639847.1	c.112G>A	p.Val38Met	missense_variant	3/3	5		P1

Frequencies

GnomAD3 genomes AF: 0.000374 AC: 57 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000407 AC: 101 AN: 247906 Hom.: 0 AF XY: 0.000482 AC XY: 65 AN XY: 134942

Gnomad AFR exome AF: 0.000261

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000848

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.00116 AC: 1690 AN: 1460964 Hom.: 3 Cov.: 30 AF XY: 0.00107 AC XY: 775 AN XY: 726742

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000379

Gnomad4 NFE exome AF: 0.00147

Gnomad4 OTH exome AF: 0.000729

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152224 Hom.: 0 Cov.: 33 AF XY: 0.000390 AC XY: 29 AN XY: 74370

Gnomad4 AFR AF: 0.000338

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000617

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000804 Hom.: 0

Bravo AF: 0.000468

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000500 AC: 2

ESP6500EA AF: 0.000600 AC: 5

ExAC AF: 0.000298 AC: 36

EpiCase AF: 0.000927

EpiControl AF: 0.00101

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 38 of the MC1R protein (p.Val38Met). This variant is present in population databases (rs200050206, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with melanoma (PMID: 16982779, 19585506, 22095472, 23647022, 24982914). ClinVar contains an entry for this variant (Variation ID: 406211). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects MC1R function (PMID: 19338054, 21749400). 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. -
Uncertain significance, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Tyrosinase-positive oculocutaneous albinism;C1849452:Skin/hair/eye pigmentation, variation in, 2;C2751295:Melanoma, cutaneous malignant, susceptibility to, 5;C2751296:Increased analgesia from kappa-opioid receptor agonist, female-specific Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 26, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Benign	17
Dann	Uncertain	0.99
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.91	D;.;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-0.55	T
MutationTaster	Benign	0.63	N;N
PROVEAN	Benign	-0.76	N;.;N;N
REVEL	Uncertain	0.35
Sift	Uncertain	0.012	D;.;D;D
Sift4G	Benign	0.17	T;.;T;T
Polyphen		0.0060	.;B;B;.
Vest4		0.30
MVP		0.73
MPC		0.017
ClinPred		0.049	T
GERP RS		3.5
Varity_R		0.12
gMVP		0.26

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: rs200050206; hg19: chr16-89985778;