rs1805008

Variant names:

• chr16-89919736-C-T
• rs1805008
• NM_002386.4:c.478C>T
• MC1R p.Arg160Trp

Your query was ambiguous. Multiple possible variants found:

• chr16-89919736-C-T
• chr16-89919736-C-A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002386.4(MC1R):​c.478C>T​(p.Arg160Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0685 in 1,606,068 control chromosomes in the GnomAD database, including 4,568 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. R160Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.046 (207 hom., cov: 33)
  • Exomes 𝑓: 0.071 (4361 hom.)
• Consequence: MC1R NM_002386.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:7 O:3
• Conservation: PhyloP100: 1.23
• Publications: 404 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057244897).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0754 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MC1R	NM_002386.4	MANE Select	c.478C>T	p.Arg160Trp	missense	Exon 1 of 1	NP_002377.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MC1R	ENST00000555147.2	TSL:6 MANE Select	c.478C>T	p.Arg160Trp	missense	Exon 1 of 1	ENSP00000451605.1	Q01726
	ENSG00000198211	ENST00000556922.1	TSL:2	c.478C>T	p.Arg160Trp	missense	Exon 1 of 5	ENSP00000451560.1	A0A0B4J269
	MC1R	ENST00000555427.1	TSL:5	c.478C>T	p.Arg160Trp	missense	Exon 3 of 4	ENSP00000451760.1	G3V4F0

Frequencies

GnomAD3 genomes AF: 0.0463 AC: 7051 AN: 152244 Hom.: 207 Cov.: 33

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.0135

Gnomad ASJ AF: 0.0599

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.0610

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0772

Gnomad OTH AF: 0.0287

GnomAD2 exomes AF: 0.0472 AC: 11354 AN: 240724 AF XY: 0.0467

Gnomad AFR exome AF: 0.0129

Gnomad AMR exome AF: 0.00819

Gnomad ASJ exome AF: 0.0579

Gnomad EAS exome AF: 0.0000558

Gnomad FIN exome AF: 0.0643

Gnomad NFE exome AF: 0.0800

Gnomad OTH exome AF: 0.0427

GnomAD4 exome AF: 0.0708 AC: 102907 AN: 1453706 Hom.: 4361 Cov.: 36 AF XY: 0.0687 AC XY: 49732 AN XY: 723538

African (AFR) AF: 0.0106 AC: 356 AN: 33474

American (AMR) AF: 0.00830 AC: 371 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0563 AC: 1469 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00611 AC: 527 AN: 86236

European-Finnish (FIN) AF: 0.0661 AC: 3020 AN: 45664

Middle Eastern (MID) AF: 0.0172 AC: 99 AN: 5760

European-Non Finnish (NFE) AF: 0.0843 AC: 93775 AN: 1111756

Other (OTH) AF: 0.0546 AC: 3290 AN: 60306

GnomAD4 genome AF: 0.0463 AC: 7052 AN: 152362 Hom.: 207 Cov.: 33 AF XY: 0.0439 AC XY: 3270 AN XY: 74498

African (AFR) AF: 0.0133 AC: 555 AN: 41596

American (AMR) AF: 0.0135 AC: 206 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0599 AC: 208 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00497 AC: 24 AN: 4832

European-Finnish (FIN) AF: 0.0610 AC: 648 AN: 10622

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0772 AC: 5251 AN: 68032

Other (OTH) AF: 0.0284 AC: 60 AN: 2116

Alfa AF: 0.0631 Hom.: 1252

Bravo AF: 0.0412

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.0628

EpiControl AF: 0.0681

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	2	Melanoma, cutaneous malignant, susceptibility to, 5 (2)
-	-	2	not specified (2)
-	-	1	Malignant tumor of breast (1)
1	-	-	SKIN/HAIR/EYE PIGMENTATION, VARIATION IN, 2 (1)
-	-	-	ALBINISM, OCULOCUTANEOUS, TYPE II, MODIFIER OF (1)
-	-	-	Increased analgesia from kappa-opioid receptor agonist, female-specific (1)
-	-	-	Skin/hair/eye pigmentation 2, red hair/fair skin (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	0.050
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Pathogenic	4.4	H
PhyloP100		1.2
PROVEAN	Pathogenic	-7.0	D
REVEL	Benign	0.27
Sift	Uncertain	0.010	D
Sift4G	Pathogenic	0.0010	D
Varity_R		0.36
gMVP		0.65
Mutation Taster		=93/7	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1805008;

hg19: chr16-89986144;

COSMIC: COSV59625425;

COSMIC: COSV59625425;