rs11547464

Positions:

• chr16-89919683-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP4_Strong BP6_Very_Strong 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0065 (47 hom.)
• Consequence: MC1R NM_002386.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 8.07

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 -15 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).
• BP6: Variant 16-89919683-G-A is Benign according to our data. Variant chr16-89919683-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 239153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89919683-G-A is described in Lovd as [Benign]. Variant chr16-89919683-G-A is described in Lovd as [Pathogenic]. Variant chr16-89919683-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 716 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MC1R	NM_002386.4	c.425G>A	p.Arg142His	missense_variant	1/1	ENST00000555147.2	NP_002377.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MC1R	ENST00000555147.2	c.425G>A	p.Arg142His	missense_variant	1/1		NM_002386.4	ENSP00000451605	P1
MC1R	ENST00000555427.1	c.425G>A	p.Arg142His	missense_variant	3/4	5		ENSP00000451760
MC1R	ENST00000639847.1	c.425G>A	p.Arg142His	missense_variant	3/3	5		ENSP00000492011	P1

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

GnomAD3 exomes AF: 0.00532 AC: 1298 AN: 243850 Hom.: 7 AF XY: 0.00523 AC XY: 694 AN XY: 132602

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

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.: 1 Cov.: 33 AF XY: 0.00432 AC XY: 322 AN XY: 74484

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.: 5

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: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	MC1R: PP3, BS1 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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

Likely 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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

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;D;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D;.;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Benign	0.015	T;T;T;T
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	4.2	.;H;H;.
MutationTaster	Benign	1.0	D;D
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	T
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

Other links and lift over

dbSNP: rs11547464; hg19: chr16-89986091;