rs3212359

Variant names:

• chr16-89918769-C-T
• rs3212359
• ENST00000555427.1:c.-408-82C>T

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.-408-82C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.439 in 234,560 control chromosomes in the GnomAD database, including 25,068 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (16512 hom., cov: 34)
  • Exomes 𝑓: 0.42 (8556 hom.)
• Consequence: MC1R ENST00000555427.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.48
• Publications: 15 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=-0.76).
• BP6: Variant 16-89918769-C-T is Benign according to our data. Variant chr16-89918769-C-T is described in ClinVar as Benign. ClinVar VariationId is 321402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.631 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC124903759	XM_047435031.1	c.1213-82C>T		intron_variant	Intron 3 of 3		XP_047290987.1
MC1R	NM_002386.4	c.-490C>T		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.-408-82C>T		intron_variant	Intron 2 of 3	5		ENSP00000451760.1
MC1R	ENST00000639847.1	c.-408-82C>T		intron_variant	Intron 2 of 2	5		ENSP00000492011.1
MC1R	ENST00000555147.2	c.-490C>T		upstream_gene_variant		6	NM_002386.4	ENSP00000451605.1

Frequencies

GnomAD3 genomes AF: 0.449 AC: 68232 AN: 152036 Hom.: 16484 Cov.: 34

Gnomad AFR AF: 0.595

Gnomad AMI AF: 0.298

Gnomad AMR AF: 0.511

Gnomad ASJ AF: 0.339

Gnomad EAS AF: 0.651

Gnomad SAS AF: 0.552

Gnomad FIN AF: 0.442

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.332

Gnomad OTH AF: 0.430

GnomAD4 exome AF: 0.421 AC: 34680 AN: 82406 Hom.: 8556 Cov.: 0 AF XY: 0.419 AC XY: 15924 AN XY: 37982

African (AFR) AF: 0.593 AC: 2241 AN: 3778

American (AMR) AF: 0.549 AC: 1736 AN: 3164

Ashkenazi Jewish (ASJ) AF: 0.341 AC: 1718 AN: 5036

East Asian (EAS) AF: 0.795 AC: 8970 AN: 11278

South Asian (SAS) AF: 0.529 AC: 453 AN: 856

European-Finnish (FIN) AF: 0.463 AC: 37 AN: 80

Middle Eastern (MID) AF: 0.481 AC: 232 AN: 482

European-Non Finnish (NFE) AF: 0.328 AC: 16724 AN: 51004

Other (OTH) AF: 0.382 AC: 2569 AN: 6728

GnomAD4 genome AF: 0.449 AC: 68310 AN: 152154 Hom.: 16512 Cov.: 34 AF XY: 0.457 AC XY: 34009 AN XY: 74390

African (AFR) AF: 0.595 AC: 24685 AN: 41508

American (AMR) AF: 0.512 AC: 7836 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.339 AC: 1178 AN: 3470

East Asian (EAS) AF: 0.650 AC: 3357 AN: 5166

South Asian (SAS) AF: 0.551 AC: 2654 AN: 4818

European-Finnish (FIN) AF: 0.442 AC: 4687 AN: 10600

Middle Eastern (MID) AF: 0.568 AC: 167 AN: 294

European-Non Finnish (NFE) AF: 0.332 AC: 22563 AN: 67972

Other (OTH) AF: 0.431 AC: 912 AN: 2116

Alfa AF: 0.421 Hom.: 2141

Bravo AF: 0.460

Asia WGS AF: 0.564 AC: 1965 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	-0.76
CADD	Benign	0.43
DANN	Benign	0.86
PhyloP100		-3.5
PromoterAI		-0.060	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: rs3212359; hg19: chr16-89985177; COSMIC: COSV59624817; COSMIC: COSV59624817;