rs3212361

Positions:

• chr16-89918814-G-A
• chr16-89918814-G-C
• chr16-89918814-G-T

Variant summary

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

The XM_047435031.1(LOC124903759):​c.1213-37G>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: LOC124903759 XM_047435031.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.78

Genes affected

LOC124903759 (HGNC:):

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 Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
LOC124903759	XM_047435031.1	c.1213-37G>A		intron_variant			XP_047290987.1
MC1R	NM_002386.4			upstream_gene_variant		ENST00000555147.2	NP_002377.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MC1R	ENST00000555427.1	c.-408-37G>A		intron_variant		5		ENSP00000451760
MC1R	ENST00000639847.1	c.-408-37G>A		intron_variant		5		ENSP00000492011	P1
MC1R	ENST00000555147.2			upstream_gene_variant			NM_002386.4	ENSP00000451605	P1

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

Gnomad4 AFR exome AF: 0.391

Gnomad4 AMR exome AF: 0.454

Gnomad4 ASJ exome AF: 0.243

Gnomad4 EAS exome AF: 0.782

Gnomad4 SAS exome AF: 0.445

Gnomad4 FIN exome AF: 0.368

Gnomad4 NFE exome AF: 0.236

Gnomad4 OTH exome AF: 0.281

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

Gnomad4 AFR AF: 0.402

Gnomad4 AMR AF: 0.414

Gnomad4 ASJ AF: 0.243

Gnomad4 EAS AF: 0.645

Gnomad4 SAS AF: 0.457

Gnomad4 FIN AF: 0.411

Gnomad4 NFE AF: 0.252

Gnomad4 OTH AF: 0.309

Alfa AF: 0.268 Hom.: 9365

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

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	7.2
DANN	Benign	0.94

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