16-89919773-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_002386.4(MC1R):c.515G>T(p.Ser172Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000348 in 1,608,628 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts 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. S172T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00036 ( 10 hom. )

Consequence

MC1R
NM_002386.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1B:3

Conservation

PhyloP100: 8.07

Publications

9 publications found

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 was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01643169).

BP6

Variant 16-89919773-G-T is Benign according to our data. Variant chr16-89919773-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 321430.

BS2

High AC in GnomAd4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MC1R	NM_002386.4 link	c.515G>T	p.Ser172Ile	missense_variant	Exon 1 of 1	ENST00000555147.2	NP_002377.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MC1R	ENST00000555147.2 link	c.515G>T	p.Ser172Ile	missense_variant	Exon 1 of 1	6	NM_002386.4	ENSP00000451605.1
ENSG00000198211	ENST00000556922.1 link	c.515G>T	p.Ser172Ile	missense_variant	Exon 1 of 5	2		ENSP00000451560.1

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00372

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000676

AC:

166

AN:

245522

AF XY:

0.00106

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000998

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000713

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000361

AC:

526

AN:

1456252

Hom.:

Cov.:

AF XY:

0.000548

AC XY:

397

AN XY:

724644

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00494

AC:

426

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48098

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000729

AC:

AN:

1111802

Other (OTH)

AF:

0.000265

AC:

AN:

60320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

124

165

206

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000223

AC:

AN:

152376

Hom.:

Cov.:

AF XY:

0.000295

AC XY:

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41590

American (AMR)

AF:

0.0000653

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00373

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000220

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.527

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000159

Hom.:

Bravo

AF:

0.000136

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000750

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Tyrosinase-positive oculocutaneous albinism

Pathogenic:1Uncertain:1Benign:1

Sep 22, 2015

Yale Center for Mendelian Genomics, Yale University

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Sep 01, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

May 22, 2022

3billion

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed as homozygous in at least two unrelated individuals/adults in the gnomAD v.2.1.1 dataset and therefore considered benign. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MC1R- related disorder (ClinVar ID: VCV000321430). However, the evidence of pathogenicity is insufficient at this time with conflicting interpretations of pathogenicity. Therefore, this variant is classified as uncertain significanceaccording to the recommendation of ACMG/AMP guideline. -

Skin and Hair Hypopigmentation

Pathogenic:1

Sep 22, 2015

University of Washington Center for Mendelian Genomics, University of Washington

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Melanoma, cutaneous malignant, susceptibility to, 5

Benign:1

Sep 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Malignant Melanoma Susceptibility

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

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

Uncertain

0.53

BayesDel_addAF

Benign

-0.059

BayesDel_noAF

Pathogenic

0.14

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.45

.;T;T;.

Eigen

Pathogenic

0.78

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;.;D;D

M_CAP

Benign

0.064

MetaRNN

Benign

0.016

T;T;T;T

MetaSVM

Uncertain

0.35

MutationAssessor

Pathogenic

4.4

.;H;H;.

PhyloP100

8.1

PROVEAN

Uncertain

-3.2

D;.;D;N

REVEL

Uncertain

0.52

Sift

Pathogenic

0.0

D;.;D;D

Sift4G

Uncertain

0.040

D;.;D;D

Polyphen

1.0

.;D;D;.

Vest4

0.83

MVP

0.85

MPC

0.12

ClinPred

0.24

GERP RS

4.7

Varity_R

0.79

gMVP

0.64

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over