Genetic Variant MC1R:c.-580-116C>A (chr16-89917760-C-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The ENST00000570217.1(ENSG00000267048):n.202-116C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00377 in 181,014 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0044 ( 15 hom., cov: 33)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

ENSG00000267048
ENST00000570217.1 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.33

Publications

0 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:

LOC124903759 (HGNC:):

LOC124903759 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 16-89917760-C-A is Benign according to our data. Variant chr16-89917760-C-A is described in ClinVar as Benign. ClinVar VariationId is 1287143.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 15 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000570217.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MC1R	ENST00000555427.1	TSL:5	c.-580-116C>A	intron	N/A	ENSP00000451760.1	G3V4F0
MC1R	ENST00000639847.1	TSL:5	c.-580-116C>A	intron	N/A	ENSP00000492011.1	Q01726
ENSG00000267048	ENST00000570217.1	TSL:4	n.202-116C>A	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00445

AC:

677

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0540

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00140

Gnomad OTH

AF:

0.00239

GnomAD4 exome

AF:

0.000243

AC:

AN:

28748

Hom.:

AF XY:

0.000151

AC XY:

AN XY:

13208

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

950

American (AMR)

AF:

0.00

AC:

AN:

622

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1836

East Asian (EAS)

AF:

0.000337

AC:

AN:

5938

South Asian (SAS)

AF:

0.00

AC:

AN:

236

European-Finnish (FIN)

AF:

0.0417

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

182

European-Non Finnish (NFE)

AF:

0.000241

AC:

AN:

16626

Other (OTH)

AF:

0.00

AC:

AN:

2334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.532

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00444

AC:

676

AN:

152266

Hom.:

Cov.:

AF XY:

0.00660

AC XY:

491

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41552

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0540

AC:

572

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00140

AC:

AN:

68020

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

100

134

167

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00397

Hom.:

Bravo

AF:

0.000329

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.25

(source)

DANN

Benign

0.57

PhyloP100

-1.3

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over