rs885479

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002386.4(MC1R):c.488G>A(p.Arg163Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0824 in 1,607,552 control chromosomes in the GnomAD database, including 19,024 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.091 ( 2038 hom., cov: 33)

Exomes 𝑓: 0.082 ( 16986 hom. )

Consequence

MC1R
NM_002386.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.07

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.213233E-5).

BP6

Variant 16-89919746-G-A is Benign according to our data. Variant chr16-89919746-G-A is described in ClinVar as [Benign]. Clinvar id is 258652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89919746-G-A is described in Lovd as [Benign]. Variant chr16-89919746-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.62 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MC1R	NM_002386.4 linkuse as main transcript	c.488G>A	p.Arg163Gln	missense_variant	1/1	ENST00000555147.2	NP_002377.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
MC1R	ENST00000555147.2 linkuse as main transcript	c.488G>A	p.Arg163Gln	missense_variant	1/1		NM_002386.4	ENSP00000451605	P1
MC1R	ENST00000555427.1 linkuse as main transcript	c.488G>A	p.Arg163Gln	missense_variant	3/4	5		ENSP00000451760
MC1R	ENST00000639847.1 linkuse as main transcript	c.488G>A	p.Arg163Gln	missense_variant	3/3	5		ENSP00000492011	P1

Frequencies

GnomAD3 genomes

AF:

0.0913

AC:

13896

AN:

152166

Hom.:

2038

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0172

Gnomad AMI

AF:

0.00440

Gnomad AMR

AF:

0.234

Gnomad ASJ

AF:

0.0334

Gnomad EAS

AF:

0.639

Gnomad SAS

AF:

0.0546

Gnomad FIN

AF:

0.231

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0486

Gnomad OTH

AF:

0.0788

GnomAD3 exomes

AF:

0.152

AC:

37008

AN:

244212

Hom.:

7445

AF XY:

0.135

AC XY:

17960

AN XY:

133154

show subpopulations

Gnomad AFR exome

AF:

0.0166

Gnomad AMR exome

AF:

0.397

Gnomad ASJ exome

AF:

0.0344

Gnomad EAS exome

AF:

0.640

Gnomad SAS exome

AF:

0.0375

Gnomad FIN exome

AF:

0.227

Gnomad NFE exome

AF:

0.0482

Gnomad OTH exome

AF:

0.111

GnomAD4 exome

AF:

0.0815

AC:

118637

AN:

1455268

Hom.:

16986

Cov.:

AF XY:

0.0786

AC XY:

56958

AN XY:

724254

show subpopulations

Gnomad4 AFR exome

AF:

0.0125

Gnomad4 AMR exome

AF:

0.377

Gnomad4 ASJ exome

AF:

0.0342

Gnomad4 EAS exome

AF:

0.718

Gnomad4 SAS exome

AF:

0.0436

Gnomad4 FIN exome

AF:

0.213

Gnomad4 NFE exome

AF:

0.0475

Gnomad4 OTH exome

AF:

0.0865

GnomAD4 genome

AF:

0.0913

AC:

13896

AN:

152284

Hom.:

2038

Cov.:

AF XY:

0.105

AC XY:

7844

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.0172

Gnomad4 AMR

AF:

0.234

Gnomad4 ASJ

AF:

0.0334

Gnomad4 EAS

AF:

0.638

Gnomad4 SAS

AF:

0.0542

Gnomad4 FIN

AF:

0.231

Gnomad4 NFE

AF:

0.0486

Gnomad4 OTH

AF:

0.0775

Alfa

AF:

0.0657

Hom.:

1994

Bravo

AF:

0.0957

TwinsUK

AF:

0.0378

AC:

140

ALSPAC

AF:

0.0423

AC:

163

ESP6500AA

AF:

0.0153

AC:

ESP6500EA

AF:

0.0482

AC:

414

ExAC

AF:

0.134

AC:

16230

Asia WGS

AF:

0.293

AC:

1022

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Melanoma, cutaneous malignant, susceptibility to, 5

Benign:2

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 rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	This variant is associated with the following publications: (PMID: 22547573, 30414346, 30531825, 29178624, 11487574, 21052032, 24335900, 22854540, 18366057, 17616515, 11875032, 23711066, 24660985, 23647022, 22464597) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Tyrosinase-positive oculocutaneous albinism;C1849452:Skin/hair/eye pigmentation, variation in, 2;C2751295:Melanoma, cutaneous malignant, susceptibility to, 5;C2751296:Increased analgesia from kappa-opioid receptor agonist, female-specific

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 14, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.083

.;T;T;.

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.77

T;.;T;T

MetaRNN

Benign

0.000032

T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.9

.;L;L;.

MutationTaster

Benign

1.0

P;P

PROVEAN

Benign

-0.42

N;.;N;N

REVEL

Benign

0.16

Sift

Benign

0.035

D;.;T;D

Sift4G

Benign

0.30

T;.;T;T

Polyphen

0.0040

.;B;B;.

Vest4

0.052

MPC

0.017

ClinPred

0.0049

GERP RS

4.8

Varity_R

0.10

gMVP

0.32

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