16-89919895-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_002386.4(MC1R):c.637C>T(p.Arg213Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00047 in 1,606,972 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R213Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00070 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00045 (0 hom.)
• Consequence: MC1R NM_002386.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.29

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018007338).
• BP6: Variant 16-89919895-C-T is Benign according to our data. Variant chr16-89919895-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 321435.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High AC in GnomAd at 106 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MC1R	NM_002386.4	c.637C>T	p.Arg213Trp	missense_variant	1/1	ENST00000555147.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MC1R	ENST00000555147.2	c.637C>T	p.Arg213Trp	missense_variant	1/1		NM_002386.4	P1
	ENST00000554623.1	n.917G>A		non_coding_transcript_exon_variant	2/2	3
MC1R	ENST00000555427.1	c.637C>T	p.Arg213Trp	missense_variant	3/4	5
MC1R	ENST00000639847.1	c.637C>T	p.Arg213Trp	missense_variant	3/3	5		P1

Frequencies

GnomAD3 genomes AF: 0.000696 AC: 106 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000916

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000348 AC: 84 AN: 241070 Hom.: 0 AF XY: 0.000357 AC XY: 47 AN XY: 131710

Gnomad AFR exome AF: 0.000596

Gnomad AMR exome AF: 0.000466

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000982

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000504

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.000446 AC: 649 AN: 1454656 Hom.: 0 Cov.: 35 AF XY: 0.000431 AC XY: 312 AN XY: 723856

Gnomad4 AFR exome AF: 0.000837

Gnomad4 AMR exome AF: 0.000403

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.0000213

Gnomad4 NFE exome AF: 0.000501

Gnomad4 OTH exome AF: 0.000531

GnomAD4 genome AF: 0.000696 AC: 106 AN: 152316 Hom.: 0 Cov.: 33 AF XY: 0.000550 AC XY: 41 AN XY: 74496

Gnomad4 AFR AF: 0.000914

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000368 Hom.: 0

Bravo AF: 0.000888

ESP6500AA AF: 0.000239 AC: 1

ESP6500EA AF: 0.000594 AC: 5

ExAC AF: 0.000339 AC: 41

EpiCase AF: 0.000927

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Melanoma, cutaneous malignant, susceptibility to, 5 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 213 of the MC1R protein (p.Arg213Trp). This variant is present in population databases (rs200000734, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with melanoma (PMID: 15221796, 15998953, 18067130, 19799798, 23360207, 23522749, 23647022, 24982914, 25284244). ClinVar contains an entry for this variant (Variation ID: 321435). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MC1R protein function. 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. -
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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.81	T;.;T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.018	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	0.82	N;N
PROVEAN	Benign	-1.3	N;.;N;N
REVEL	Benign	0.15
Sift	Uncertain	0.0040	D;.;D;D
Sift4G	Uncertain	0.010	D;.;D;D
Polyphen		0.019	.;B;B;.
Vest4		0.44
MVP		0.72
MPC		0.019
ClinPred		0.073	T
GERP RS		2.6
Varity_R		0.21
gMVP		0.65

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

Other links and lift over

dbSNP: rs200000734; hg19: chr16-89986303; COSMIC: COSV59624794; COSMIC: COSV59624794;