rs1805005

Positions:

• chr16-89919436-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BA1

The NM_002386.4(MC1R):​c.178G>T​(p.Val60Leu) variant causes a missense change. The variant allele was found at a frequency of 0.106 in 1,613,224 control chromosomes in the GnomAD database, including 11,236 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V60?) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.080 (782 hom., cov: 33)
  • Exomes 𝑓: 0.11 (10454 hom.)
• Consequence: MC1R NM_002386.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 3.88

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 -18 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-89919436-G-Y is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.0017996728).
• BP6: Variant 16-89919436-G-T is Benign according to our data. Variant chr16-89919436-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 14311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89919436-G-T is described in Lovd as [Benign]. Variant chr16-89919436-G-T is described in Lovd as [Likely_pathogenic].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MC1R	NM_002386.4	c.178G>T	p.Val60Leu	missense_variant	1/1	ENST00000555147.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MC1R	ENST00000555147.2	c.178G>T	p.Val60Leu	missense_variant	1/1		NM_002386.4	P1
MC1R	ENST00000555427.1	c.178G>T	p.Val60Leu	missense_variant	3/4	5
MC1R	ENST00000639847.1	c.178G>T	p.Val60Leu	missense_variant	3/3	5		P1

Frequencies

GnomAD3 genomes AF: 0.0803 AC: 12226 AN: 152162 Hom.: 782 Cov.: 33

Gnomad AFR AF: 0.0207

Gnomad AMI AF: 0.165

Gnomad AMR AF: 0.0817

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.0560

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.111

GnomAD3 exomes AF: 0.0860 AC: 21392 AN: 248798 Hom.: 1467 AF XY: 0.0852 AC XY: 11518 AN XY: 135146

Gnomad AFR exome AF: 0.0178

Gnomad AMR exome AF: 0.0636

Gnomad ASJ exome AF: 0.288

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.0116

Gnomad FIN exome AF: 0.0571

Gnomad NFE exome AF: 0.122

Gnomad OTH exome AF: 0.116

GnomAD4 exome AF: 0.109 AC: 159401 AN: 1460944 Hom.: 10454 Cov.: 31 AF XY: 0.106 AC XY: 77330 AN XY: 726744

Gnomad4 AFR exome AF: 0.0179

Gnomad4 AMR exome AF: 0.0661

Gnomad4 ASJ exome AF: 0.292

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0124

Gnomad4 FIN exome AF: 0.0585

Gnomad4 NFE exome AF: 0.123

Gnomad4 OTH exome AF: 0.119

GnomAD4 genome AF: 0.0803 AC: 12226 AN: 152280 Hom.: 782 Cov.: 33 AF XY: 0.0751 AC XY: 5589 AN XY: 74458

Gnomad4 AFR AF: 0.0207

Gnomad4 AMR AF: 0.0815

Gnomad4 ASJ AF: 0.304

Gnomad4 EAS AF: 0.00155

Gnomad4 SAS AF: 0.0116

Gnomad4 FIN AF: 0.0560

Gnomad4 NFE AF: 0.117

Gnomad4 OTH AF: 0.111

Alfa AF: 0.127 Hom.: 2022

Bravo AF: 0.0830

TwinsUK AF: 0.118 AC: 438

ALSPAC AF: 0.124 AC: 478

ESP6500AA AF: 0.0226 AC: 98

ESP6500EA AF: 0.133 AC: 1137

ExAC AF: 0.0826 AC: 10010

Asia WGS AF: 0.0130 AC: 44 AN: 3478

EpiCase AF: 0.142

EpiControl AF: 0.139

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6 Other:1

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	Invitae	Feb 01, 2024	- -
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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 09, 2016

- -

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, 31382929, 30531825, 27251790, 26103569, 9302268, 19077144, 20876876, 24335900, 18366057, 17616515, 11875032, 24660985, 24665948, 23647022, 10403794, 22464597) -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Center of Medical Genetics and Primary Health Care

-

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 21, 2022

- -

Skin/hair/eye pigmentation 2, blond hair/fair skin Other:1

association, no assertion criteria provided

literature only

OMIM

Oct 01, 1997

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	23
DANN	Uncertain	1.0
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.71	T;.;T;T
MetaRNN	Benign	0.0018	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	0.0085	P;P
PROVEAN	Benign	-1.7	N;.;N;N
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Benign	0.14	T;.;T;D
Polyphen		0.99	.;D;D;.
Vest4		0.48
MutPred		0.21		Loss of catalytic residue at V60 (P = 0.0973);Loss of catalytic residue at V60 (P = 0.0973);Loss of catalytic residue at V60 (P = 0.0973);Loss of catalytic residue at V60 (P = 0.0973);
MPC		0.13
ClinPred		0.037	T
GERP RS		4.9
Varity_R		0.53
gMVP		0.25

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: rs1805005; hg19: chr16-89985844; COSMIC: COSV59624824; COSMIC: COSV59624824;