16-89920138-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP3BP4_StrongBP6BS1BS2

The NM_002386.4(MC1R):c.880G>C(p.Asp294His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0181 in 1,613,770 control chromosomes in the GnomAD database, including 366 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,risk factor (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D294Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.011 ( 28 hom., cov: 33)

Exomes 𝑓: 0.019 ( 338 hom. )

Consequence

MC1R
NM_002386.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity; risk factor criteria provided, conflicting classifications P:2U:1B:7O:2

Conservation

PhyloP100: 9.84

Publications

309 publications found

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 was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 6: BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.010107994).

BP6

Variant 16-89920138-G-C is Benign according to our data. Variant chr16-89920138-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity|risk_factor. ClinVar VariationId is 14307.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0109 (1658/152138) while in subpopulation NFE AF = 0.0182 (1240/67986). AF 95% confidence interval is 0.0174. There are 28 homozygotes in GnomAd4. There are 717 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1658 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MC1R	NM_002386.4	MANE Select	c.880G>C	p.Asp294His	missense	Exon 1 of 1	NP_002377.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MC1R	ENST00000555147.2	TSL:6 MANE Select	c.880G>C	p.Asp294His	missense	Exon 1 of 1	ENSP00000451605.1	Q01726
ENSG00000198211	ENST00000556922.1	TSL:2	c.880G>C	p.Asp294His	missense	Exon 1 of 5	ENSP00000451560.1	A0A0B4J269
MC1R	ENST00000555427.1	TSL:5	c.880G>C	p.Asp294His	missense	Exon 3 of 4	ENSP00000451760.1	G3V4F0

Frequencies

GnomAD3 genomes

AF:

0.0109

AC:

1658

AN:

152022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00413

Gnomad AMI

AF:

0.0242

Gnomad AMR

AF:

0.0116

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00170

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0182

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.00909

AC:

2263

AN:

249066

AF XY:

0.00905

show subpopulations

Gnomad AFR exome

AF:

0.00311

Gnomad AMR exome

AF:

0.00730

Gnomad ASJ exome

AF:

0.00169

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00200

Gnomad NFE exome

AF:

0.0163

Gnomad OTH exome

AF:

0.0112

GnomAD4 exome

AF:

0.0188

AC:

27485

AN:

1461632

Hom.:

338

Cov.:

AF XY:

0.0181

AC XY:

13181

AN XY:

727096

show subpopulations

African (AFR)

AF:

0.00275

AC:

AN:

33480

American (AMR)

AF:

0.00742

AC:

332

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00222

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00229

AC:

122

AN:

53362

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0231

AC:

25700

AN:

1111836

Other (OTH)

AF:

0.0193

AC:

1165

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

1583

3166

4749

6332

7915

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1050

2100

3150

4200

5250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0109

AC:

1658

AN:

152138

Hom.:

Cov.:

AF XY:

0.00964

AC XY:

717

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.00414

AC:

172

AN:

41500

American (AMR)

AF:

0.0116

AC:

177

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00170

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0182

AC:

1240

AN:

67986

Other (OTH)

AF:

0.0109

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

178

267

356

445

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0137

Hom.:

Bravo

AF:

0.0118

TwinsUK

AF:

0.0221

AC:

ALSPAC

AF:

0.0221

AC:

ESP6500AA

AF:

0.00686

AC:

ESP6500EA

AF:

0.0207

AC:

176

ExAC

AF:

0.00853

AC:

1033

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0182

EpiControl

AF:

0.0187

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity; risk factor

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Melanoma, cutaneous malignant, susceptibility to, 5 (2)

MC1R-related disorder (1)

Skin and Hair Hypopigmentation (1)

Tyrosinase-positive oculocutaneous albinism (1)

Melanoma (1)

Skin/hair/eye pigmentation 2, red hair/fair skin (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Uncertain

0.082

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.84

MetaRNN

Benign

0.010

MetaSVM

Uncertain

0.25

MutationAssessor

Pathogenic

3.5

PhyloP100

9.8

PROVEAN

Pathogenic

-5.8

REVEL

Uncertain

0.61

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.93

MVP

0.93

MPC

0.13

ClinPred

0.064

GERP RS

5.3

Varity_R

0.88

gMVP

0.81

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over