rs201326893

Positions:

chr16-89919714-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PVS1_StrongBS2

The NM_002386.4(MC1R):c.456C>A(p.Tyr152Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00054 in 1,606,408 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00054 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00054 ( 5 hom. )

Consequence

MC1R
NM_002386.4 stop_gained

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.38

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 Uncertain_significance. Variant got 0 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.

BS2

High AC in GnomAd4 at 83 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MC1R	NM_002386.4 linkuse as main transcript	c.456C>A	p.Tyr152Ter	stop_gained	1/1	ENST00000555147.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
MC1R	ENST00000555147.2 linkuse as main transcript	c.456C>A	p.Tyr152Ter	stop_gained	1/1		NM_002386.4	P1
MC1R	ENST00000555427.1 linkuse as main transcript	c.456C>A	p.Tyr152Ter	stop_gained	3/4	5
MC1R	ENST00000639847.1 linkuse as main transcript	c.456C>A	p.Tyr152Ter	stop_gained	3/3	5		P1

Frequencies

GnomAD3 genomes

AF:

0.000545

AC:

AN:

152264

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.0138

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000367

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000840

AC:

204

AN:

242812

Hom.:

AF XY:

0.000870

AC XY:

115

AN XY:

132240

show subpopulations

Gnomad AFR exome

AF:

0.0000632

Gnomad AMR exome

AF:

0.000493

Gnomad ASJ exome

AF:

0.0109

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000608

Gnomad OTH exome

AF:

0.00149

GnomAD4 exome

AF:

0.000539

AC:

784

AN:

1454026

Hom.:

Cov.:

AF XY:

0.000547

AC XY:

396

AN XY:

723708

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000581

Gnomad4 ASJ exome

AF:

0.0105

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000653

Gnomad4 NFE exome

AF:

0.000332

Gnomad4 OTH exome

AF:

0.00158

GnomAD4 genome

AF:

0.000545

AC:

AN:

152382

Hom.:

Cov.:

AF XY:

0.000564

AC XY:

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.0138

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000367

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00145

Hom.:

Bravo

AF:

0.000525

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000676

AC:

EpiCase

AF:

0.000872

EpiControl

AF:

0.000948

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

Likely 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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change creates a premature translational stop signal (p.Tyr152*) in the MC1R gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 166 amino acid(s) of the MC1R protein. This variant is present in population databases (rs201326893, gnomAD 1.0%), and has an allele count higher than expected for a pathogenic variant. This variant has been reported in individuals affected with melanoma (PMID: 23522749, 15998953, 19269164, 17496785, 31382929), as well as unaffected individuals (PMID: 15221796, 19585506, 19269164). lt has been observed more frequently in individuals with red hair and pale skin phenotypes (PMID: 11933208, 17316231). Pigmentation of the hair and skin is correlated with ultraviolet sensitivity and skin cancer. Other loss-of-function missense variants in MC1R have been correlated with lighter skin pigmentation (PMID: 11030758) and possibly increased melanoma risk, although no definitive disease association has been concluded (PMID: 18366057, 21128237). ClinVar contains an entry for this variant (Variation ID: 265230). 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 28, 2018

Nonsense variant predicted to result in protein truncation in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; This variant is associated with the following publications: (PMID: 11933208, 34662886, 16567973, 15998953, 30531825, 31382929, 26689913, 34426522, 23711066, 17496785) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.90

MutationTaster

Benign

1.0

A;D

Vest4

0.20

GERP RS

2.4

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