rs11547464

Variant names:

• chr16-89919683-G-A
• rs11547464
• NM_002386.4:c.425G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3 BP4_Strong BP6 BS2

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R142C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0047 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0065 (47 hom.)
• Consequence: MC1R NM_002386.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 8.07
• Publications: 187 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 -8 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 10: BayesDel_addAF, BayesDel_noAF, Dann, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when AlphaMissense, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.015277147).
• BP6: Variant 16-89919683-G-A is Benign according to our data. Variant chr16-89919683-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 239153.
• BS2: High AC in GnomAd4 at 716 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002386.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MC1R	NM_002386.4	MANE Select	c.425G>A	p.Arg142His	missense	Exon 1 of 1	NP_002377.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MC1R	ENST00000555147.2	TSL:6 MANE Select	c.425G>A	p.Arg142His	missense	Exon 1 of 1	ENSP00000451605.1
	ENSG00000198211	ENST00000556922.1	TSL:2	c.425G>A	p.Arg142His	missense	Exon 1 of 5	ENSP00000451560.1
	MC1R	ENST00000555427.1	TSL:5	c.425G>A	p.Arg142His	missense	Exon 3 of 4	ENSP00000451760.1

Frequencies

GnomAD3 genomes AF: 0.00471 AC: 717 AN: 152210 Hom.: 1 Cov.: 33

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

GnomAD2 exomes AF: 0.00532 AC: 1298 AN: 243850 AF XY: 0.00523

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 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.: 47 Cov.: 33 AF XY: 0.00629 AC XY: 4551 AN XY: 723480

African (AFR) AF: 0.000926 AC: 31 AN: 33470

American (AMR) AF: 0.00675 AC: 302 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0177 AC: 462 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39678

South Asian (SAS) AF: 0.000243 AC: 21 AN: 86244

European-Finnish (FIN) AF: 0.00128 AC: 59 AN: 46008

Middle Eastern (MID) AF: 0.0132 AC: 76 AN: 5766

European-Non Finnish (NFE) AF: 0.00721 AC: 8019 AN: 1111444

Other (OTH) AF: 0.00687 AC: 414 AN: 60304

GnomAD4 genome AF: 0.00470 AC: 716 AN: 152328 Hom.: 1 Cov.: 33 AF XY: 0.00432 AC XY: 322 AN XY: 74484

African (AFR) AF: 0.00139 AC: 58 AN: 41578

American (AMR) AF: 0.00666 AC: 102 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0181 AC: 63 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.000376 AC: 4 AN: 10628

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00687 AC: 467 AN: 68012

Other (OTH) AF: 0.00803 AC: 17 AN: 2116

Alfa AF: 0.00668 Hom.: 13

Bravo AF: 0.00560

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00744 AC: 64

ExAC AF: 0.00495 AC: 601

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00867

EpiControl AF: 0.00960

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:6

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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

Aug 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MC1R: PP3, BS2

Oct 26, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 variant’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.

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

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.

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.54
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Benign	0.015	T
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		8.1
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MVP		0.98
MPC		0.13
ClinPred		0.11	T
GERP RS		4.8
Varity_R		0.88
gMVP		0.78
Mutation Taster		=90/10	polymorphism

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: rs11547464; hg19: chr16-89986091;