rs1555623887

Variant names:

• chr16-89920058-G-A
• NM_002386.4:c.800G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-89920058-G-A
• chr16-89920058-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002386.4(MC1R):​c.800G>A​(p.Cys267Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MC1R NM_002386.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.92

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MC1R	NM_002386.4	c.800G>A	p.Cys267Tyr	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.800G>A	p.Cys267Tyr	missense_variant	Exon 1 of 1	6	NM_002386.4	ENSP00000451605.1
ENSG00000198211	ENST00000556922.1	c.800G>A	p.Cys267Tyr	missense_variant	Exon 1 of 5	2		ENSP00000451560.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Apr 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 267 of the MC1R protein (p.Cys267Tyr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MC1R-related conditions. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MC1R protein function. 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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Uncertain	0.45	.;T;T;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D;.;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Benign	-0.41	T
MutationAssessor	Pathogenic	3.3	.;M;M;.
PROVEAN	Pathogenic	-10	D;.;D;N
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0030	D;.;D;D
Sift4G	Uncertain	0.052	T;.;T;D
Polyphen		0.12	.;B;B;.
Vest4		0.95
MutPred		0.83		Gain of catalytic residue at P271 (P = 0.0643);Gain of catalytic residue at P271 (P = 0.0643);Gain of catalytic residue at P271 (P = 0.0643);Gain of catalytic residue at P271 (P = 0.0643);
MVP		0.87
MPC		0.035
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.88
gMVP		0.47

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-89986466;