16-89919523-G-C

Position:

chr16-89919523-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002386.4(MC1R):c.265G>C(p.Gly89Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000775 in 1,612,924 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000077 ( 1 hom. )

Consequence

MC1R
NM_002386.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:2U:4

Conservation

PhyloP100: 0.302

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.121064425).

BS2

High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MC1R	NM_002386.4 linkuse as main transcript	c.265G>C	p.Gly89Arg	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.265G>C	p.Gly89Arg	missense_variant	1/1		NM_002386.4	ENSP00000451605	P1
MC1R	ENST00000555427.1 linkuse as main transcript	c.265G>C	p.Gly89Arg	missense_variant	3/4	5		ENSP00000451760
MC1R	ENST00000639847.1 linkuse as main transcript	c.265G>C	p.Gly89Arg	missense_variant	3/3	5		ENSP00000492011	P1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000604

AC:

AN:

248484

Hom.:

AF XY:

0.0000519

AC XY:

AN XY:

134918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000116

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000767

AC:

112

AN:

1460720

Hom.:

Cov.:

AF XY:

0.0000840

AC XY:

AN XY:

726604

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000190

Gnomad4 NFE exome

AF:

0.0000918

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000255

Hom.:

Bravo

AF:

0.0000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Melanoma, cutaneous malignant, susceptibility to, 5

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 13, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 89 of the MC1R protein (p.Gly89Arg). This variant is present in population databases (rs34540312, gnomAD 0.01%). This missense change has been observed in individual(s) with melanoma (PMID: 17072629, 23522749, 24335900). ClinVar contains an entry for this variant (Variation ID: 449207). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MC1R protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects MC1R function (PMID: 23522749). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 28, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Tyrosinase-positive oculocutaneous albinism

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Sep 22, 2015

- -

Skin and Hair Hypopigmentation

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

Sep 22, 2015

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 23, 2017

The G89R variant in the MC1R gene has been reported previously as a heterozygous variant in a patient with melanoma, and in a large family where homozyogus family members had hypopigmentation (Puig-Butille et al., 2013; Shahzad et al., 2015). The G89R variant is observed in 18/126318 (0.014%) alleles from individuals of non-Finnish European background, in large population cohorts (Lek et al., 2016). The G89R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved across species. Functional studies showed that the receptor protein with G89R variant has complete loss of function and three dimensional in silico analysis predicts that G89R affected protein folding (Ozola et al., 2013; Ibarrola-Villaga et al., 2014). We interpret G89R as a variant of uncertain significance. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.51

CADD

Benign

6.1

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

.;T;T;.

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.13

LIST_S2

Uncertain

0.96

D;.;D;D

M_CAP

Benign

0.015

MetaRNN

Benign

0.12

T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.3

.;L;L;.

MutationTaster

Benign

1.0

N;N

PROVEAN

Benign

0.13

N;.;N;N

REVEL

Benign

0.066

Sift

Uncertain

0.019

D;.;D;D

Sift4G

Uncertain

0.010

D;.;D;D

Polyphen

0.56

.;P;P;.

Vest4

0.30

MVP

0.42

MPC

0.037

ClinPred

0.096

GERP RS

0.48

Varity_R

0.31

gMVP

0.51

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