rs61996344

chr16-89919391-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002386.4(MC1R):c.133T>C(p.Phe45Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000355 in 1,613,310 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 Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: MC1R NM_002386.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.05

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05549863).
• BP6: Variant 16-89919391-T-C is Benign according to our data. Variant chr16-89919391-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 470702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 57 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MC1R	NM_002386.4	c.133T>C	p.Phe45Leu	missense_variant	1/1	ENST00000555147.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MC1R	ENST00000555147.2	c.133T>C	p.Phe45Leu	missense_variant	1/1		NM_002386.4	P1
MC1R	ENST00000555427.1	c.133T>C	p.Phe45Leu	missense_variant	3/4	5
MC1R	ENST00000639847.1	c.133T>C	p.Phe45Leu	missense_variant	3/3	5		P1

Frequencies

GnomAD3 genomes AF: 0.000375 AC: 57 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000455 AC: 113 AN: 248514 Hom.: 0 AF XY: 0.000437 AC XY: 59 AN XY: 135114

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00319

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000543

Gnomad OTH exome AF: 0.000663

GnomAD4 exome AF: 0.000352 AC: 515 AN: 1461012 Hom.: 0 Cov.: 30 AF XY: 0.000381 AC XY: 277 AN XY: 726780

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.00249

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000336

Gnomad4 OTH exome AF: 0.000729

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152298 Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23 AN XY: 74462

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000471

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000733 Hom.: 1

Bravo AF: 0.000514

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000715 AC: 6

ExAC AF: 0.000422 AC: 51

EpiCase AF: 0.000382

EpiControl AF: 0.000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Melanoma, cutaneous malignant, susceptibility to, 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 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. 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. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.14
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.77	T;.;T;T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.055	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D
PROVEAN	Pathogenic	-5.3	D;.;D;N
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Uncertain	0.0020	D;.;D;D
Polyphen		0.99	.;D;D;.
Vest4		0.44
MutPred		0.74		Gain of stability (P = 0.4553);Gain of stability (P = 0.4553);Gain of stability (P = 0.4553);Gain of stability (P = 0.4553);
MVP		0.74
MPC		0.13
ClinPred		0.14	T
GERP RS		4.9
Varity_R		0.75
gMVP		0.42

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: rs61996344; hg19: chr16-89985799; COSMIC: COSV59626895; COSMIC: COSV59626895;