16-89917962-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The XM_047435031.1(LOC124903759):c.1127T>C(p.Leu376Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.572 in 225,376 control chromosomes in the GnomAD database, including 41,467 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/5 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (29907 hom., cov: 34)
  • Exomes 𝑓: 0.53 (11560 hom.)
• Consequence: LOC124903759 XM_047435031.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0740

Genes affected

LOC124903759 (HGNC:):

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 16-89917962-T-C is Benign according to our data. Variant chr16-89917962-T-C is described in ClinVar as [Benign]. Clinvar id is 321379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.896 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOC124903759	XM_047435031.1	c.1127T>C	p.Leu376Pro	missense_variant	3/4
LOC124903759	XM_047435032.1	c.*117T>C		3_prime_UTR_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MC1R	ENST00000555427.1	c.-494T>C		5_prime_UTR_variant	2/4	5
MC1R	ENST00000639847.1	c.-494T>C		5_prime_UTR_variant	2/3	5		P1

Frequencies

GnomAD3 genomes AF: 0.594 AC: 90283 AN: 152042 Hom.: 29851 Cov.: 34

Gnomad AFR AF: 0.865

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.587

Gnomad ASJ AF: 0.405

Gnomad EAS AF: 0.917

Gnomad SAS AF: 0.679

Gnomad FIN AF: 0.518

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.425

Gnomad OTH AF: 0.548

GnomAD4 exome AF: 0.526 AC: 38511 AN: 73216 Hom.: 11560 Cov.: 0 AF XY: 0.520 AC XY: 17653 AN XY: 33926

Gnomad4 AFR exome AF: 0.866

Gnomad4 AMR exome AF: 0.624

Gnomad4 ASJ exome AF: 0.404

Gnomad4 EAS exome AF: 0.913

Gnomad4 SAS exome AF: 0.653

Gnomad4 FIN exome AF: 0.547

Gnomad4 NFE exome AF: 0.418

Gnomad4 OTH exome AF: 0.508

GnomAD4 genome AF: 0.594 AC: 90399 AN: 152160 Hom.: 29907 Cov.: 34 AF XY: 0.599 AC XY: 44577 AN XY: 74404

Gnomad4 AFR AF: 0.865

Gnomad4 AMR AF: 0.587

Gnomad4 ASJ AF: 0.405

Gnomad4 EAS AF: 0.917

Gnomad4 SAS AF: 0.678

Gnomad4 FIN AF: 0.518

Gnomad4 NFE AF: 0.425

Gnomad4 OTH AF: 0.551

Alfa AF: 0.449 Hom.: 17355

Bravo AF: 0.611

Asia WGS AF: 0.774 AC: 2694 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Melanoma, cutaneous malignant, susceptibility to, 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This 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 provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 10, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	5.7
Dann	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs3212354; hg19: chr16-89984370; COSMIC: COSV73353723; COSMIC: COSV73353723;