16-89918814-G-A

Variant names:

• chr16-89918814-G-A
• rs3212361
• ENST00000555427.1:c.-408-37G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000555427.1(MC1R):​c.-408-37G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 238,202 control chromosomes in the GnomAD database, including 15,897 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9608 hom., cov: 33)
  • Exomes 𝑓: 0.33 (6289 hom.)
• Consequence: MC1R ENST00000555427.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.78
• Publications: 13 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]

LOC124903759 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 16-89918814-G-A is Benign according to our data. Variant chr16-89918814-G-A is described in ClinVar as Benign. ClinVar VariationId is 321404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.627 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC124903759	XM_047435031.1	c.1213-37G>A		intron_variant	Intron 3 of 3		XP_047290987.1
MC1R	NM_002386.4	c.-445G>A		upstream_gene_variant		ENST00000555147.2	NP_002377.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MC1R	ENST00000555427.1	c.-408-37G>A		intron_variant	Intron 2 of 3	5		ENSP00000451760.1
MC1R	ENST00000639847.1	c.-408-37G>A		intron_variant	Intron 2 of 2	5		ENSP00000492011.1
MC1R	ENST00000555147.2	c.-445G>A		upstream_gene_variant		6	NM_002386.4	ENSP00000451605.1

Frequencies

GnomAD3 genomes AF: 0.340 AC: 51779 AN: 152092 Hom.: 9589 Cov.: 33

Gnomad AFR AF: 0.401

Gnomad AMI AF: 0.243

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.243

Gnomad EAS AF: 0.646

Gnomad SAS AF: 0.459

Gnomad FIN AF: 0.411

Gnomad MID AF: 0.296

Gnomad NFE AF: 0.252

Gnomad OTH AF: 0.306

GnomAD4 exome AF: 0.332 AC: 28576 AN: 85992 Hom.: 6289 Cov.: 0 AF XY: 0.332 AC XY: 13245 AN XY: 39844

African (AFR) AF: 0.391 AC: 1525 AN: 3896

American (AMR) AF: 0.454 AC: 1688 AN: 3720

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 1252 AN: 5142

East Asian (EAS) AF: 0.782 AC: 8933 AN: 11424

South Asian (SAS) AF: 0.445 AC: 453 AN: 1018

European-Finnish (FIN) AF: 0.368 AC: 53 AN: 144

Middle Eastern (MID) AF: 0.293 AC: 144 AN: 492

European-Non Finnish (NFE) AF: 0.236 AC: 12589 AN: 53252

Other (OTH) AF: 0.281 AC: 1939 AN: 6904

GnomAD4 genome AF: 0.341 AC: 51838 AN: 152210 Hom.: 9608 Cov.: 33 AF XY: 0.354 AC XY: 26323 AN XY: 74418

African (AFR) AF: 0.402 AC: 16683 AN: 41538

American (AMR) AF: 0.414 AC: 6330 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 842 AN: 3468

East Asian (EAS) AF: 0.645 AC: 3338 AN: 5172

South Asian (SAS) AF: 0.457 AC: 2204 AN: 4824

European-Finnish (FIN) AF: 0.411 AC: 4358 AN: 10610

Middle Eastern (MID) AF: 0.291 AC: 85 AN: 292

European-Non Finnish (NFE) AF: 0.252 AC: 17123 AN: 67978

Other (OTH) AF: 0.309 AC: 653 AN: 2116

Alfa AF: 0.284 Hom.: 25728

Bravo AF: 0.345

Asia WGS AF: 0.506 AC: 1762 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	7.2
DANN	Benign	0.94
PhyloP100		1.8
PromoterAI		-0.057	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs3212361; hg19: chr16-89985222; COSMIC: COSV59624822; COSMIC: COSV59624822;