rs1555623867

Positions:

• chr16-89919955-C-CA

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_002386.4(MC1R):​c.698dup​(p.Phe235LeufsTer4) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000685 in 1,460,014 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Q233Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MC1R NM_002386.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.28

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]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.269 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MC1R	NM_002386.4	c.698dup	p.Phe235LeufsTer4	frameshift_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.698dup	p.Phe235LeufsTer4	frameshift_variant	1/1		NM_002386.4	ENSP00000451605	P1
	ENST00000554623.1	n.856_857insT		non_coding_transcript_exon_variant	2/2	3
MC1R	ENST00000555427.1	c.698dup	p.Phe235LeufsTer4	frameshift_variant	3/4	5		ENSP00000451760
MC1R	ENST00000639847.1	c.698dup	p.Phe235LeufsTer4	frameshift_variant	3/3	5		ENSP00000492011	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460014 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 726330

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 18, 2017

In summary, this is a novel loss-of-function variant in a gene in which other loss-of-function variants have a suggested association with increased melanoma risk. However, the relative disease risk of this variant has not been assessed. Therefore, it has been classified as a Variant of Uncertain Significance. Other loss-of-function missense variants in MC1R have been correlated with lighter skin pigmentation (PMID: 11030758) and possibly increased melanoma risk, although no definitive disease association has been concluded (PMID: 18366057, 21128237). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an MC1R-related disease. Experimental studies have not been reported for this truncating variant, and it is currently unknown if the last 83 amino acids of the MC1R protein are critical for its function. This sequence change inserts 1 nucleotide in the single exon of the MC1R mRNA (c.698dupA), causing a frameshift at codon 235. This creates a premature translational stop signal in the MC1R mRNA (p.Phe235Leufs*4). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 83 amino acids of the MC1R protein. -

Computational scores

Source: dbNSFP v4.3

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: rs1555623867; hg19: chr16-89986363;