rs885479

chr16-89919746-G-Achr16-89919746-G-C

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.488G>A(p.Arg163Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0824 in 1,607,552 control chromosomes in the GnomAD database, including 19,024 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.091 (2038 hom., cov: 33)
  • Exomes 𝑓: 0.082 (16986 hom.)
• Consequence: MC1R NM_002386.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.07

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.213233E-5).
• BP6: Variant 16-89919746-G-A is Benign according to our data. Variant chr16-89919746-G-A is described in ClinVar as [Benign]. Clinvar id is 258652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89919746-G-A is described in Lovd as [Benign]. Variant chr16-89919746-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.62 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MC1R	NM_002386.4	c.488G>A	p.Arg163Gln	missense_variant	1/1	ENST00000555147.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MC1R	ENST00000555147.2	c.488G>A	p.Arg163Gln	missense_variant	1/1		NM_002386.4	P1
MC1R	ENST00000555427.1	c.488G>A	p.Arg163Gln	missense_variant	3/4	5
MC1R	ENST00000639847.1	c.488G>A	p.Arg163Gln	missense_variant	3/3	5		P1

Frequencies

GnomAD3 genomes AF: 0.0913 AC: 13896 AN: 152166 Hom.: 2038 Cov.: 33

Gnomad AFR AF: 0.0172

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.0334

Gnomad EAS AF: 0.639

Gnomad SAS AF: 0.0546

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0486

Gnomad OTH AF: 0.0788

GnomAD3 exomes AF: 0.152 AC: 37008 AN: 244212 Hom.: 7445 AF XY: 0.135 AC XY: 17960 AN XY: 133154

Gnomad AFR exome AF: 0.0166

Gnomad AMR exome AF: 0.397

Gnomad ASJ exome AF: 0.0344

Gnomad EAS exome AF: 0.640

Gnomad SAS exome AF: 0.0375

Gnomad FIN exome AF: 0.227

Gnomad NFE exome AF: 0.0482

Gnomad OTH exome AF: 0.111

GnomAD4 exome AF: 0.0815 AC: 118637 AN: 1455268 Hom.: 16986 Cov.: 36 AF XY: 0.0786 AC XY: 56958 AN XY: 724254

Gnomad4 AFR exome AF: 0.0125

Gnomad4 AMR exome AF: 0.377

Gnomad4 ASJ exome AF: 0.0342

Gnomad4 EAS exome AF: 0.718

Gnomad4 SAS exome AF: 0.0436

Gnomad4 FIN exome AF: 0.213

Gnomad4 NFE exome AF: 0.0475

Gnomad4 OTH exome AF: 0.0865

GnomAD4 genome AF: 0.0913 AC: 13896 AN: 152284 Hom.: 2038 Cov.: 33 AF XY: 0.105 AC XY: 7844 AN XY: 74440

Gnomad4 AFR AF: 0.0172

Gnomad4 AMR AF: 0.234

Gnomad4 ASJ AF: 0.0334

Gnomad4 EAS AF: 0.638

Gnomad4 SAS AF: 0.0542

Gnomad4 FIN AF: 0.231

Gnomad4 NFE AF: 0.0486

Gnomad4 OTH AF: 0.0775

Alfa AF: 0.0657 Hom.: 1994

Bravo AF: 0.0957

TwinsUK AF: 0.0378 AC: 140

ALSPAC AF: 0.0423 AC: 163

ESP6500AA AF: 0.0153 AC: 67

ESP6500EA AF: 0.0482 AC: 414

ExAC AF: 0.134 AC: 16230

Asia WGS AF: 0.293 AC: 1022 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Melanoma, cutaneous malignant, susceptibility to, 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 22, 2018

This variant is associated with the following publications: (PMID: 22547573, 30414346, 30531825, 29178624, 11487574, 21052032, 24335900, 22854540, 18366057, 17616515, 11875032, 23711066, 24660985, 23647022, 22464597) -

Tyrosinase-positive oculocutaneous albinism;C1849452:Skin/hair/eye pigmentation, variation in, 2;C2751295:Melanoma, cutaneous malignant, susceptibility to, 5;C2751296:Increased analgesia from kappa-opioid receptor agonist, female-specific Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 14, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	14
Dann	Uncertain	0.99
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.77	T;.;T;T
MetaRNN	Benign	0.000032	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	P;P
PROVEAN	Benign	-0.42	N;.;N;N
REVEL	Benign	0.16
Sift	Benign	0.035	D;.;T;D
Sift4G	Benign	0.30	T;.;T;T
Polyphen		0.0040	.;B;B;.
Vest4		0.052
MPC		0.017
ClinPred		0.0049	T
GERP RS		4.8
Varity_R		0.10
gMVP		0.32

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: rs885479; hg19: chr16-89986154; COSMIC: COSV59624988; COSMIC: COSV59624988;