rs3212371

Positions:

• chr16-89920793-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002386.4(MC1R):​c.*581A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 675,172 control chromosomes in the GnomAD database, including 7,328 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.16 (2647 hom., cov: 32)
  • Exomes 𝑓: 0.12 (4681 hom.)
• Consequence: MC1R NM_002386.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0200

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 16-89920793-A-G is Benign according to our data. Variant chr16-89920793-A-G is described in ClinVar as [Benign]. Clinvar id is 321454.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MC1R	NM_002386.4	c.*581A>G		3_prime_UTR_variant	1/1	ENST00000555147.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MC1R	ENST00000555147.2	c.*581A>G		3_prime_UTR_variant	1/1		NM_002386.4	P1
	ENST00000554623.1	n.87-68T>C		intron_variant, non_coding_transcript_variant		3
MC1R	ENST00000555427.1	c.*5A>G		3_prime_UTR_variant	4/4	5
MC1R	ENST00000639847.1	c.*581A>G		3_prime_UTR_variant	3/3	5		P1

Frequencies

GnomAD3 genomes AF: 0.163 AC: 24749 AN: 151928 Hom.: 2631 Cov.: 32

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.0626

Gnomad AMR AF: 0.0902

Gnomad ASJ AF: 0.0843

Gnomad EAS AF: 0.270

Gnomad SAS AF: 0.210

Gnomad FIN AF: 0.0807

Gnomad MID AF: 0.0637

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.138

GnomAD3 exomes AF: 0.133 AC: 14839 AN: 111224 Hom.: 1324 AF XY: 0.136 AC XY: 7905 AN XY: 58334

Gnomad AFR exome AF: 0.299

Gnomad AMR exome AF: 0.0719

Gnomad ASJ exome AF: 0.0784

Gnomad EAS exome AF: 0.279

Gnomad SAS exome AF: 0.188

Gnomad FIN exome AF: 0.0817

Gnomad NFE exome AF: 0.109

Gnomad OTH exome AF: 0.106

GnomAD4 exome AF: 0.120 AC: 63028 AN: 523126 Hom.: 4681 Cov.: 0 AF XY: 0.123 AC XY: 34522 AN XY: 280376

Gnomad4 AFR exome AF: 0.293

Gnomad4 AMR exome AF: 0.0703

Gnomad4 ASJ exome AF: 0.0768

Gnomad4 EAS exome AF: 0.169

Gnomad4 SAS exome AF: 0.184

Gnomad4 FIN exome AF: 0.0806

Gnomad4 NFE exome AF: 0.108

Gnomad4 OTH exome AF: 0.136

GnomAD4 genome AF: 0.163 AC: 24801 AN: 152046 Hom.: 2647 Cov.: 32 AF XY: 0.159 AC XY: 11809 AN XY: 74340

Gnomad4 AFR AF: 0.287

Gnomad4 AMR AF: 0.0901

Gnomad4 ASJ AF: 0.0843

Gnomad4 EAS AF: 0.271

Gnomad4 SAS AF: 0.210

Gnomad4 FIN AF: 0.0807

Gnomad4 NFE AF: 0.112

Gnomad4 OTH AF: 0.140

Alfa AF: 0.120 Hom.: 1404

Bravo AF: 0.165

Asia WGS AF: 0.252 AC: 873 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.4
DANN	Benign	0.63

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: rs3212371; hg19: chr16-89987201;