chr16-89919477-G-C

Variant names:

• chr16-89919477-G-C
• rs755918287
• NM_002386.4:c.219G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002386.4(MC1R):​c.219G>C​(p.Met73Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,460,978 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M73V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MC1R NM_002386.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.33
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MC1R	NM_002386.4	c.219G>C	p.Met73Ile	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.219G>C	p.Met73Ile	missense_variant	Exon 1 of 1	6	NM_002386.4	ENSP00000451605.1
ENSG00000198211	ENST00000556922.1	c.219G>C	p.Met73Ile	missense_variant	Exon 1 of 5	2		ENSP00000451560.1
MC1R	ENST00000555427.1	c.219G>C	p.Met73Ile	missense_variant	Exon 3 of 4	5		ENSP00000451760.1
MC1R	ENST00000639847.1	c.219G>C	p.Met73Ile	missense_variant	Exon 3 of 3	5		ENSP00000492011.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460978 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726758

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52716

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111842

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	.;T;T;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.91	D;.;D;D
M_CAP	Benign	0.025	D
MetaRNN	Uncertain	0.45	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.2	.;M;M;.
PhyloP100		6.3
PROVEAN	Uncertain	-3.6	D;.;D;N
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Uncertain	0.0020	D;.;D;D
Polyphen		0.18	.;B;B;.
Vest4		0.65
MutPred		0.60		Gain of glycosylation at S71 (P = 0.1438);Gain of glycosylation at S71 (P = 0.1438);Gain of glycosylation at S71 (P = 0.1438);Gain of glycosylation at S71 (P = 0.1438);
MVP		0.56
MPC		0.043
ClinPred		0.99	D
GERP RS		4.9
PromoterAI		0.0072	Neutral
Varity_R		0.92
gMVP		0.39
Mutation Taster		=65/35	polymorphism

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

Other links and lift over

dbSNP: rs755918287; hg19: chr16-89985885;