rs201533137

Positions:

• chr16-89919325-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PVS1_Strong BP6 BS2

The NM_002386.4(MC1R):​c.67C>T​(p.Gln23Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000251 in 1,612,270 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: MC1R NM_002386.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.0310

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 -1 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. There are 11 pathogenic variants in the truncated region.
• BP6: Variant 16-89919325-C-T is Benign according to our data. Variant chr16-89919325-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 239159.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}.
• BS2: High AC in GnomAd4 at 200 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MC1R	NM_002386.4	c.67C>T	p.Gln23Ter	stop_gained	1/1	ENST00000555147.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MC1R	ENST00000555147.2	c.67C>T	p.Gln23Ter	stop_gained	1/1		NM_002386.4	P1
MC1R	ENST00000555427.1	c.67C>T	p.Gln23Ter	stop_gained	3/4	5
MC1R	ENST00000639847.1	c.67C>T	p.Gln23Ter	stop_gained	3/3	5		P1

Frequencies

GnomAD3 genomes AF: 0.00132 AC: 201 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00478

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000304 AC: 74 AN: 243538 Hom.: 1 AF XY: 0.000248 AC XY: 33 AN XY: 133056

Gnomad AFR exome AF: 0.00459

Gnomad AMR exome AF: 0.0000878

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: 0.0000274

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000140 AC: 204 AN: 1459956 Hom.: 1 Cov.: 30 AF XY: 0.000117 AC XY: 85 AN XY: 726246

Gnomad4 AFR exome AF: 0.00523

Gnomad4 AMR exome AF: 0.000135

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.00131 AC: 200 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.00126 AC XY: 94 AN XY: 74484

Gnomad4 AFR AF: 0.00474

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000591 Hom.: 0

Bravo AF: 0.00143

ESP6500AA AF: 0.00291 AC: 11

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000406 AC: 49

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 18, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2020	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 295 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Observed in one patient from a cohort of individuals at risk for pancreatic cancer, however, additional clinical details and family history were not provided (Smith er al., 2016); This variant is associated with the following publications: (PMID: 26546047, 12839583) -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 05, 2024

This sequence change creates a premature translational stop signal (p.Gln23*) in the MC1R gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 295 amino acid(s) of the MC1R protein. This variant is present in population databases (rs201533137, gnomAD 0.5%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with clinical features of MC1R-related conditions (PMID: 12839583). ClinVar contains an entry for this variant (Variation ID: 239159). 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
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	31
DANN	Uncertain	0.98
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.15	N
MutationTaster	Benign	1.0	A;D
Vest4		0.063
GERP RS		-5.6

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: rs201533137; hg19: chr16-89985733;