rs1805005

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 3.88

Variant links:

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]

MC1R links:

ENSG00000198211 (HGNC:):

ENSG00000198211 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
MC1R	NM_002386.4 link	c.178G>T	p.Val60Leu	missense_variant	Exon 1 of 1	ENST00000555147.2	NP_002377.4	Q01726Q1JUL4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MC1R	ENST00000555147.2 link	c.178G>T	p.Val60Leu	missense_variant	Exon 1 of 1	6	NM_002386.4	ENSP00000451605.1	Q01726
ENSG00000198211	ENST00000556922.1 link	c.178G>T	p.Val60Leu	missense_variant	Exon 1 of 5	2		ENSP00000451560.1	A0A0B4J269
MC1R	ENST00000555427.1 link	c.178G>T	p.Val60Leu	missense_variant	Exon 3 of 4	5		ENSP00000451760.1	G3V4F0
MC1R	ENST00000639847.1 link	c.178G>T	p.Val60Leu	missense_variant	Exon 3 of 3	5		ENSP00000492011.1	Q01726

Frequencies

GnomAD3 genomes

AF:

0.0803

AC:

12226

AN:

152162

Hom.:

782

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.106

AC XY:

77330

AN XY:

726744

show subpopulations

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.:

AF XY:

0.0751

AC XY:

5589

AN XY:

74458

show subpopulations

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:

ESP6500EA

AF:

0.133

AC:

1137

ExAC

AF:

0.0826

AC:

10010

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.142

EpiControl

AF:

0.139

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

.;T;T;.

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.71

T;.;T;T

MetaRNN

Benign

0.0018

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.1

.;L;L;.

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over