rs3212369

Positions:

• chr16-89920352-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002386.4(MC1R):​c.*140A>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 0.174 in 756,892 control chromosomes in the GnomAD database, including 13,290 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4352 hom., cov: 32)
  • Exomes 𝑓: 0.16 (8938 hom.)
• Consequence: MC1R NM_002386.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.774

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-89920352-A-G is Benign according to our data. Variant chr16-89920352-A-G is described in ClinVar as [Benign]. Clinvar id is 321444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.36 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MC1R	NM_002386.4	c.*140A>G		3_prime_UTR_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.*140A>G		3_prime_UTR_variant	1/1	6	NM_002386.4	ENSP00000451605.1
ENSG00000198211	ENST00000556922.1	c.950+144A>G		intron_variant		2		ENSP00000451560.1

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33349 AN: 152006 Hom.: 4344 Cov.: 32

Gnomad AFR AF: 0.365

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.268

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.170

Gnomad OTH AF: 0.213

GnomAD4 exome AF: 0.163 AC: 98548 AN: 604768 Hom.: 8938 Cov.: 7 AF XY: 0.161 AC XY: 50284 AN XY: 312582

Gnomad4 AFR exome AF: 0.364

Gnomad4 AMR exome AF: 0.128

Gnomad4 ASJ exome AF: 0.154

Gnomad4 EAS exome AF: 0.172

Gnomad4 SAS exome AF: 0.117

Gnomad4 FIN exome AF: 0.106

Gnomad4 NFE exome AF: 0.166

Gnomad4 OTH exome AF: 0.193

GnomAD4 genome AF: 0.219 AC: 33377 AN: 152124 Hom.: 4352 Cov.: 32 AF XY: 0.211 AC XY: 15679 AN XY: 74376

Gnomad4 AFR AF: 0.365

Gnomad4 AMR AF: 0.158

Gnomad4 ASJ AF: 0.154

Gnomad4 EAS AF: 0.269

Gnomad4 SAS AF: 0.126

Gnomad4 FIN AF: 0.104

Gnomad4 NFE AF: 0.170

Gnomad4 OTH AF: 0.212

Alfa AF: 0.202 Hom.: 1847

Bravo AF: 0.231

Asia WGS AF: 0.214 AC: 746 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	-0.87
CADD	Benign	3.1
DANN	Benign	0.57

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: rs3212369; hg19: chr16-89986760; COSMIC: COSV59624658; COSMIC: COSV59624658;