rs368507952

Positions:

chr16-89920175-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_002386.4(MC1R):c.917G>A(p.Arg306His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000344 in 1,613,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00036 ( 0 hom. )

Consequence

MC1R
NM_002386.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 8.06

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17943954).

BP6

Variant 16-89920175-G-A is Benign according to our data. Variant chr16-89920175-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 470716.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.

BS2

High AC in GnomAd4 at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MC1R	NM_002386.4 linkuse as main transcript	c.917G>A	p.Arg306His	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.917G>A	p.Arg306His	missense_variant	1/1		NM_002386.4	ENSP00000451605	P1
	ENST00000554623.1 linkuse as main transcript	n.637C>T		non_coding_transcript_exon_variant	2/2	3
MC1R	ENST00000555427.1 linkuse as main transcript	c.917G>A	p.Arg306His	missense_variant	3/4	5		ENSP00000451760
MC1R	ENST00000639847.1 linkuse as main transcript	c.917G>A	p.Arg306His	missense_variant	3/3	5		ENSP00000492011	P1

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000245

AC:

AN:

248962

Hom.:

AF XY:

0.000311

AC XY:

AN XY:

135172

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00105

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000213

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.000361

AC:

528

AN:

1461654

Hom.:

Cov.:

AF XY:

0.000385

AC XY:

280

AN XY:

727110

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000846

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000380

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.000184

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00103

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000250

Hom.:

Bravo

AF:

0.000166

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000591

AC:

ExAC

AF:

0.000231

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Melanoma, cutaneous malignant, susceptibility to, 5

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 08, 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 306 of the MC1R protein (p.Arg306His). This variant is present in population databases (rs368507952, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with melanoma (PMID: 16982779, 19269164, 23312576, 23360207, 24982914). It has also been observed to segregate with oculocutaneous albinism in a single family (PMID: 23312576), but the clinical significance of this finding is uncertain. ClinVar contains an entry for this variant (Variation ID: 470716). 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 expected to disrupt MC1R protein function with a positive predictive value of 80%. 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. -

Tyrosinase-positive oculocutaneous albinism

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

3billion

May 22, 2022

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.023%) but quite commonly in the south asian population (0.1%). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MC1R- related disorder (PMID: 16645598). However, the evidence of pathogenicity is insufficient at this time and there are conflicting interpretations of pathogenicity (Clinvar ID: VCV000470716). Therefore, this variant is classified as uncertain significanceaccording to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.067

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.66

.;D;D;.

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.99

D;.;D;D

M_CAP

Uncertain

0.086

MetaRNN

Benign

0.18

T;T;T;T

MetaSVM

Uncertain

0.016

MutationAssessor

Pathogenic

4.3

.;H;H;.

MutationTaster

Benign

1.0

D;D

PROVEAN

Uncertain

-3.7

D;.;D;N

REVEL

Uncertain

0.47

Sift

Uncertain

0.0010

D;.;D;D

Sift4G

Pathogenic

0.0010

D;.;D;D

Polyphen

1.0

.;D;D;.

Vest4

0.83

MVP

0.90

MPC

0.12

ClinPred

0.41

GERP RS

4.3

Varity_R

0.62

gMVP

0.85

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