16-89919683-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3BP4_StrongBS2

The NM_002386.4(MC1R):c.425G>A(p.Arg142His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00629 in 1,606,080 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0047 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0065 ( 47 hom. )

Consequence

MC1R
NM_002386.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 8.07

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 -7 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 9: BayesDel_addAF, BayesDel_noAF, Dann, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when AlphaMissense, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.015277147).

BS2

High AC in GnomAd4 at 716 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MC1R	NM_002386.4 link	c.425G>A	p.Arg142His	missense_variant	Exon 1 of 1	ENST00000555147.2	NP_002377.4	Q01726Q1JUL4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MC1R	ENST00000555147.2 link	c.425G>A	p.Arg142His	missense_variant	Exon 1 of 1	6	NM_002386.4	ENSP00000451605.1		Q01726
ENSG00000198211	ENST00000556922.1 link	c.425G>A	p.Arg142His	missense_variant	Exon 1 of 5	2		ENSP00000451560.1		A0A0B4J269

Frequencies

GnomAD3 genomes

AF:

0.00471

AC:

717

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00140

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00667

Gnomad ASJ

AF:

0.0181

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000376

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00688

Gnomad OTH

AF:

0.00812

GnomAD3 exomes

AF:

0.00532

AC:

1298

AN:

243850

Hom.:

AF XY:

0.00523

AC XY:

694

AN XY:

132602

show subpopulations

Gnomad AFR exome

AF:

0.000937

Gnomad AMR exome

AF:

0.00681

Gnomad ASJ exome

AF:

0.0164

Gnomad EAS exome

AF:

0.0000557

Gnomad SAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.00147

Gnomad NFE exome

AF:

0.00697

Gnomad OTH exome

AF:

0.0116

GnomAD4 exome

AF:

0.00646

AC:

9385

AN:

1453752

Hom.:

Cov.:

AF XY:

0.00629

AC XY:

4551

AN XY:

723480

show subpopulations

Gnomad4 AFR exome

AF:

0.000926

Gnomad4 AMR exome

AF:

0.00675

Gnomad4 ASJ exome

AF:

0.0177

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000243

Gnomad4 FIN exome

AF:

0.00128

Gnomad4 NFE exome

AF:

0.00721

Gnomad4 OTH exome

AF:

0.00687

GnomAD4 genome

AF:

0.00470

AC:

716

AN:

152328

Hom.:

Cov.:

AF XY:

0.00432

AC XY:

322

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00139

Gnomad4 AMR

AF:

0.00666

Gnomad4 ASJ

AF:

0.0181

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000376

Gnomad4 NFE

AF:

0.00687

Gnomad4 OTH

AF:

0.00803

Alfa

AF:

0.00727

Hom.:

Bravo

AF:

0.00560

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.00744

AC:

ExAC

AF:

0.00495

AC:

601

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00867

EpiControl

AF:

0.00960

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:6

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MC1R p.Arg142His variant was identified in dbSNP (ID: rs11547464) as "With Likely benign allele" and in ClinVar (classified as benign and likely benign by Invitae and Illumina, respectively; associated conditions are Cutaneous malignant melanoma 5 and Malignant Melanoma Susceptibility). The variant was not identified in Cosmic. The variant was also found in control databases in 1414 of 275224 chromosomes (7 homozygous) at a frequency of 0.005138 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 172 of 10318 chromosomes (freq: 0.01667), Other in 72 of 7130 chromosomes (freq: 0.0101), European (non-Finnish) in 874 of 127818 chromosomes (freq: 0.006838), Latino in 239 of 35340 chromosomes (freq: 0.006763), European (Finnish) in 27 of 19814 chromosomes (freq: 0.001363), African in 24 of 24718 chromosomes (freq: 0.000971), South Asian in 5 of 30578 chromosomes (freq: 0.000164), and East Asian in 1 of 19508 chromosomes (freq: 0.000051). The p.R142H variant is classified as a strong-R allele for the Red Hair Colour (RHC) phenotype (Morgan_2018_PMID: 30531825; Williams_2011_PMID: 21128237). The literature is inconsistent with regards to the p.R142H variantâ€šÃ„Ã´s association with cutaneous melanoma (Williams_2011_PMID: 21128237; Artomov_2017_PMID: 29522175; Raimondi_2008_PMID: 18366057). One in vitro study showed the p.R142H variant has conserved binding properties but strongly impaired coupling to the cAMP generation system leading to red hair colour (Schioth_1999_PMID: 10403794). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Arg142 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Oct 26, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MC1R: PP3, BS2 -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Melanoma, cutaneous malignant, susceptibility to, 5

Benign:2

Jan 31, 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: Likely 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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified

Uncertain:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.54

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.70

.;D;D;.

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.86

D;.;D;D

M_CAP

Pathogenic

0.60

MetaRNN

Benign

0.015

T;T;T;T

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

4.2

.;H;H;.

PROVEAN

Pathogenic

-4.9

D;.;D;N

REVEL

Pathogenic

0.76

Sift

Pathogenic

0.0

D;.;D;D

Sift4G

Pathogenic

0.0

D;.;D;D

Polyphen

1.0

.;D;D;.

Vest4

0.96

MVP

0.98

MPC

0.13

ClinPred

0.11

GERP RS

4.8

Varity_R

0.88

gMVP

0.78

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