16-89920138-G-C

Position:

chr16-89920138-G-C

Variant summary

Our verdict is Benign. Variant got -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).

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

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 made for transcript

Verdict is Benign. Variant got -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 id is 14307.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, risk_factor=1, Benign=4}. Variant chr16-89920138-G-C is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1658 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MC1R	NM_002386.4 linkuse as main transcript	c.880G>C	p.Asp294His	missense_variant	1/1	ENST00000555147.2	NP_002377.4	Q01726Q1JUL4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MC1R	ENST00000555147.2 linkuse as main transcript	c.880G>C	p.Asp294His	missense_variant	1/1	6	NM_002386.4	ENSP00000451605.1		Q01726
ENSG00000198211	ENST00000556922.1 linkuse as main transcript	c.880G>C	p.Asp294His	missense_variant	1/5	2		ENSP00000451560.1		A0A0B4J269

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

GnomAD3 exomes

AF:

0.00909

AC:

2263

AN:

249066

Hom.:

AF XY:

0.00905

AC XY:

1223

AN XY:

135174

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 SAS 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

Gnomad4 AFR exome

AF:

0.00275

Gnomad4 AMR exome

AF:

0.00742

Gnomad4 ASJ exome

AF:

0.00222

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00229

Gnomad4 NFE exome

AF:

0.0231

Gnomad4 OTH exome

AF:

0.0193

GnomAD4 genome

AF:

0.0109

AC:

1658

AN:

152138

Hom.:

Cov.:

AF XY:

0.00964

AC XY:

717

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00414

Gnomad4 AMR

AF:

0.0116

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00170

Gnomad4 NFE

AF:

0.0182

Gnomad4 OTH

AF:

0.0109

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

Significance: Conflicting classifications of pathogenicity; risk factor

Submissions summary: Pathogenic:2Uncertain:1Benign:7Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 04, 2018	Considered a low risk allele, case control studies suggest this variant is associated with early onset cutaneous melanoma (Cust et al., 2012); Reported in association with red hair, fair skin, increased risk for melanoma, increased risk of photoaging and congenital melanocytic nevi (Puig-Butille et al., 2013; Kinsler et al., 2012; Ibarrola-Villava et al., 2014); Functional characterization of the variant show decreased ability to stimulate cAMP production, and altered cell surface expression (Schioth et al., 1999; Sanchez-Laorden et al., 2009); Observed in 920/66568 (1.4%) alleles from individuals of European background, including 6 unrelated homozygous individuals in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 22464597, 12789280, 26103569, 26197705, 10403794, 24665948, 19799798, 24660985, 11875032, 17616515, 18366057, 19452503, 22572819, 24335900, 19656326, 7581459, 23647022, 22095472, 9302268, 11179997, 30531825, 31382929, 30414346, 14709592, 11500805) -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MC1R p.Asp294His variant has been reported in the literature multiple times in association with melanoma development, red hair and fair skin (Raimondi_2008_PMID:18366057; Zorina-Lichtenwalter_2019_PMID:30657907). The variant was identified in dbSNP (ID: rs1805009), LOVD 3.0 and ClinVar (classified as benign by Invitae, as likely benign by Prevention Genetics and Illumina, as likely pathogenic by Yale Center for Mendelian Genomics and University of Washington Center for Mendelian Genomics, and as pathogenic by GeneDx). The variant was identified in control databases in 2568 of 280442 chromosomes (23 homozygous) at a frequency of 0.009157 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 2082 of 128324 chromosomes (freq: 0.01622), Other in 78 of 7136 chromosomes (freq: 0.01093), Latino in 256 of 35366 chromosomes (freq: 0.007239), African in 82 of 24150 chromosomes (freq: 0.003395), European (Finnish) in 53 of 24992 chromosomes (freq: 0.002121) and Ashkenazi Jewish in 17 of 10346 chromosomes (freq: 0.001643), but was not observed in the East Asian or South Asian populations. The p.D294H variant was found to have a dominant negative effect on MC1R cAMP signialling but had normal cell surface expression (Beaumont_2007_PMID:17616515). The p.Asp294 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. 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. 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	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 11, 2022	- -

Melanoma, cutaneous malignant, susceptibility to, 5

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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

- -

MC1R-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 08, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Skin/hair/eye pigmentation 2, red hair/fair skin

Other:1

association, no assertion criteria provided

literature only

OMIM

Nov 01, 1995

- -

Melanoma

Other:1

risk factor, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 04, 2019

MC1R c.880G>C (p.Asp294His) has been associated with increased risk for melanoma. This variant has been observed in multiple ethnic backgrounds with highest frequencies in individuals of European ancestry (1.64%, Genome Aggregation Database (gnomAD); rs1805009) and is present in ClinVar (ID: 14307). A large meta-analysis has reported an odds ratio of 1.89 [95% CI 4.8-10] for developing melanoma (Williams 2011). In vitro functional studies provide some evidence that the p.Asp294His variant may impact protein function (Beaumont 2007). In summary, this variant is not expected to cause highly penetrant Mendelian disease. p.Asp294His variant is an established risk factor for melanoma. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Uncertain

0.082

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

.;T;T;.

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.84

T;.;T;T

MetaRNN

Benign

0.010

T;T;T;T

MetaSVM

Uncertain

0.25

MutationAssessor

Pathogenic

3.5

.;H;H;.

PROVEAN

Pathogenic

-5.8

D;.;D;N

REVEL

Uncertain

0.61

Sift

Pathogenic

0.0

D;.;D;D

Sift4G

Pathogenic

0.0010

D;.;D;D

Polyphen

1.0

.;D;D;.

Vest4

0.93

MVP

0.93

MPC

0.13

ClinPred

0.064

GERP RS

5.3

Varity_R

0.88

gMVP

0.81

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