rs781549818

Variant names:

• chr16-89919278-A-G
• rs781549818
• NM_002386.4:c.20A>G

Variant summary

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

The NM_002386.4(MC1R):​c.20A>G​(p.Gln7Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000766 in 1,436,420 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000077 (0 hom.)
• Consequence: MC1R NM_002386.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.945

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]

ENSG00000198211 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.119172156).
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MC1R	NM_002386.4	c.20A>G	p.Gln7Arg	missense_variant	Exon 1 of 1	ENST00000555147.2	NP_002377.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MC1R	ENST00000555147.2	c.20A>G	p.Gln7Arg	missense_variant	Exon 1 of 1	6	NM_002386.4	ENSP00000451605.1
ENSG00000198211	ENST00000556922.1	c.20A>G	p.Gln7Arg	missense_variant	Exon 1 of 5	2		ENSP00000451560.1
MC1R	ENST00000555427.1	c.20A>G	p.Gln7Arg	missense_variant	Exon 3 of 4	5		ENSP00000451760.1
MC1R	ENST00000639847.1	c.20A>G	p.Gln7Arg	missense_variant	Exon 3 of 3	5		ENSP00000492011.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000476 AC: 1 AN: 210204 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 114754

Gnomad AFR exome AF: 0.00

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: 0.00

Gnomad NFE exome AF: 0.0000109

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000766 AC: 11 AN: 1436420 Hom.: 0 Cov.: 30 AF XY: 0.00000561 AC XY: 4 AN XY: 712474

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000819

Gnomad4 OTH exome AF: 0.0000337

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000833 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Melanoma, cutaneous malignant, susceptibility to, 5 Uncertain:1

Aug 02, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine with arginine at codon 7 of the MC1R protein (p.Gln7Arg). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and arginine. This variant is present in population databases (rs781549818, ExAC 0.006%) but has not been reported in the literature in individuals with a MC1R-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.75
DANN	Benign	0.95
DEOGEN2	Benign	0.12	.;T;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.75	T;.;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	.;M;M;.
PROVEAN	Benign	-0.97	N;.;N;N
REVEL	Benign	0.037
Sift	Uncertain	0.0010	D;.;D;D
Sift4G	Benign	0.089	T;.;T;D
Polyphen		0.034	.;B;B;.
Vest4		0.12
MVP		0.65
MPC		0.017
ClinPred		0.21	T
GERP RS		-1.4
Varity_R		0.099
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs781549818; hg19: chr16-89985686;