rs33932559

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_002386.4(MC1R):c.359T>C(p.Ile120Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00118 in 1,608,100 control chromosomes in the GnomAD database, including 18 homozygotes. 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 0.0015 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 16 hom. )

Consequence

MC1R
NM_002386.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 4.18

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01020363).

BP6

Variant 16-89919617-T-C is Benign according to our data. Variant chr16-89919617-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225411.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00153 (233/152310) while in subpopulation EAS AF= 0.038 (197/5178). AF 95% confidence interval is 0.0337. There are 2 homozygotes in gnomad4. There are 135 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 233 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MC1R	NM_002386.4 link	c.359T>C	p.Ile120Thr	missense_variant	Exon 1 of 1	ENST00000555147.2	NP_002377.4	Q01726Q1JUL4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MC1R	ENST00000555147.2 link	c.359T>C	p.Ile120Thr	missense_variant	Exon 1 of 1	6	NM_002386.4	ENSP00000451605.1		Q01726
ENSG00000198211	ENST00000556922.1 link	c.359T>C	p.Ile120Thr	missense_variant	Exon 1 of 5	2		ENSP00000451560.1		A0A0B4J269

Frequencies

GnomAD3 genomes

AF:

0.00153

AC:

233

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0382

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00314

AC:

769

AN:

245124

Hom.:

AF XY:

0.00295

AC XY:

393

AN XY:

133342

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000493

Gnomad ASJ exome

AF:

0.0000996

Gnomad EAS exome

AF:

0.0378

Gnomad SAS exome

AF:

0.00121

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000187

Gnomad OTH exome

AF:

0.00249

GnomAD4 exome

AF:

0.00115

AC:

1669

AN:

1455790

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

856

AN XY:

724538

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000403

Gnomad4 ASJ exome

AF:

0.000421

Gnomad4 EAS exome

AF:

0.0322

Gnomad4 SAS exome

AF:

0.00131

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000142

Gnomad4 OTH exome

AF:

0.00124

GnomAD4 genome

AF:

0.00153

AC:

233

AN:

152310

Hom.:

Cov.:

AF XY:

0.00181

AC XY:

135

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.0380

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00206

Hom.:

Bravo

AF:

0.00220

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00327

AC:

397

Asia WGS

AF:

0.00751

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Melanoma, cutaneous malignant, susceptibility to, 5

Uncertain:1Benign:2

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: reference population

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.37

.;T;T;.

Eigen

Benign

-0.046

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.74

T;.;T;T

MetaRNN

Benign

0.010

T;T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.8

.;L;L;.

PROVEAN

Uncertain

-3.2

D;.;D;N

REVEL

Benign

0.22

Sift

Uncertain

0.0060

D;.;D;D

Sift4G

Uncertain

0.017

D;.;D;D

Polyphen

0.66

.;P;P;.

Vest4

0.25

MVP

0.78

MPC

0.018

ClinPred

0.12

GERP RS

3.7

Varity_R

0.15

gMVP

0.34

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