rs3212368

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002386.4(MC1R):​c.*12G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00795 in 1,602,696 control chromosomes in the GnomAD database, including 944 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.043 ( 499 hom., cov: 33)
Exomes 𝑓: 0.0043 ( 445 hom. )

Consequence

MC1R
NM_002386.4 3_prime_UTR

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.35
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
BP6
Variant 16-89920224-G-A is Benign according to our data. Variant chr16-89920224-G-A is described in ClinVar as [Benign]. Clinvar id is 258650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MC1RNM_002386.4 linkuse as main transcriptc.*12G>A 3_prime_UTR_variant 1/1 ENST00000555147.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MC1RENST00000555147.2 linkuse as main transcriptc.*12G>A 3_prime_UTR_variant 1/1 NM_002386.4 P1
ENST00000554623.1 linkuse as main transcriptn.588C>T non_coding_transcript_exon_variant 2/23
MC1RENST00000639847.1 linkuse as main transcriptc.*12G>A 3_prime_UTR_variant 3/35 P1
MC1RENST00000555427.1 linkuse as main transcriptc.950+16G>A intron_variant 5

Frequencies

GnomAD3 genomes
AF:
0.0429
AC:
6536
AN:
152216
Hom.:
497
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.150
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0150
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000827
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000456
Gnomad OTH
AF:
0.0253
GnomAD3 exomes
AF:
0.0110
AC:
2718
AN:
246400
Hom.:
190
AF XY:
0.00804
AC XY:
1076
AN XY:
133888
show subpopulations
Gnomad AFR exome
AF:
0.156
Gnomad AMR exome
AF:
0.00791
Gnomad ASJ exome
AF:
0.000100
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000296
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000261
Gnomad OTH exome
AF:
0.00449
GnomAD4 exome
AF:
0.00427
AC:
6196
AN:
1450362
Hom.:
445
Cov.:
32
AF XY:
0.00360
AC XY:
2601
AN XY:
721830
show subpopulations
Gnomad4 AFR exome
AF:
0.154
Gnomad4 AMR exome
AF:
0.00855
Gnomad4 ASJ exome
AF:
0.0000384
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000395
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000104
Gnomad4 OTH exome
AF:
0.00915
GnomAD4 genome
AF:
0.0429
AC:
6541
AN:
152334
Hom.:
499
Cov.:
33
AF XY:
0.0413
AC XY:
3073
AN XY:
74494
show subpopulations
Gnomad4 AFR
AF:
0.150
Gnomad4 AMR
AF:
0.0150
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000621
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000456
Gnomad4 OTH
AF:
0.0250
Alfa
AF:
0.0364
Hom.:
122
Bravo
AF:
0.0491
Asia WGS
AF:
0.00577
AC:
21
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Melanoma, cutaneous malignant, susceptibility to, 5 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxJun 22, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.81
CADD
Benign
7.9
DANN
Benign
0.60

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.

Other links and lift over

dbSNP: rs3212368; hg19: chr16-89986632; API