rs1805005

Variant names:

• chr16-89919436-G-T
• rs1805005
• NM_002386.4:c.178G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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 (★★).

• 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:7 O:1
• Conservation: PhyloP100: 3.88
• Publications: 255 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]

ENSG00000198211 (HGNC:):

ACMG classification

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

• 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 Benign/Likely_benign. ClinVar VariationId is 14311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
MC1R	NM_002386.4	c.178G>T	p.Val60Leu	missense_variant	Exon 1 of 1	ENST00000555147.2	NP_002377.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MC1R	ENST00000555147.2	c.178G>T	p.Val60Leu	missense_variant	Exon 1 of 1	6	NM_002386.4	ENSP00000451605.1
ENSG00000198211	ENST00000556922.1	c.178G>T	p.Val60Leu	missense_variant	Exon 1 of 5	2		ENSP00000451560.1
MC1R	ENST00000555427.1	c.178G>T	p.Val60Leu	missense_variant	Exon 3 of 4	5		ENSP00000451760.1
MC1R	ENST00000639847.1	c.178G>T	p.Val60Leu	missense_variant	Exon 3 of 3	5		ENSP00000492011.1

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

GnomAD2 exomes AF: 0.0860 AC: 21392 AN: 248798 AF XY: 0.0852

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 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

African (AFR) AF: 0.0179 AC: 599 AN: 33480

American (AMR) AF: 0.0661 AC: 2958 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 7633 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0124 AC: 1068 AN: 86258

European-Finnish (FIN) AF: 0.0585 AC: 3079 AN: 52656

Middle Eastern (MID) AF: 0.101 AC: 584 AN: 5768

European-Non Finnish (NFE) AF: 0.123 AC: 136292 AN: 1111862

Other (OTH) AF: 0.119 AC: 7187 AN: 60366

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

African (AFR) AF: 0.0207 AC: 861 AN: 41578

American (AMR) AF: 0.0815 AC: 1247 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 1056 AN: 3468

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5170

South Asian (SAS) AF: 0.0116 AC: 56 AN: 4832

European-Finnish (FIN) AF: 0.0560 AC: 594 AN: 10614

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.117 AC: 7985 AN: 68008

Other (OTH) AF: 0.111 AC: 234 AN: 2114

Alfa AF: 0.112 Hom.: 3846

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:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 provided Benign:2

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Feb 09, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 21, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast Benign:1

-

Center of Medical Genetics and Primary Health Care

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Oct 01, 1997

OMIM

Significance: association

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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
DEOGEN2	Benign	0.19	.;T;T;.
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
MutationAssessor	Benign	1.1	.;L;L;.
PhyloP100		3.9
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
PromoterAI		0.00050	Neutral
Varity_R		0.53
gMVP		0.25
Mutation Taster		=99/1	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: rs1805005; hg19: chr16-89985844; COSMIC: COSV59624824; COSMIC: COSV59624824;