16-89918025-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The XM_047435031.1(LOC124903759):c.1190C>T(p.Thr397Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 228,958 control chromosomes in the GnomAD database, including 1 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 0.0012 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0010 (0 hom.)
• Consequence: LOC124903759 XM_047435031.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.84

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 16-89918025-C-T is Benign according to our data. Variant chr16-89918025-C-T is described in ClinVar as [Benign]. Clinvar id is 321385.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOC124903759	XM_047435031.1	c.1190C>T	p.Thr397Met	missense_variant	3/4
LOC124903759	XM_047435032.1	c.*180C>T		3_prime_UTR_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MC1R	ENST00000555427.1	c.-431C>T		5_prime_UTR_variant	2/4	5
MC1R	ENST00000639847.1	c.-431C>T		5_prime_UTR_variant	2/3	5		P1

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 190 AN: 152240 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00210

Gnomad OTH AF: 0.000955

GnomAD4 exome AF: 0.00104 AC: 80 AN: 76600 Hom.: 0 Cov.: 0 AF XY: 0.000906 AC XY: 32 AN XY: 35338

Gnomad4 AFR exome AF: 0.000283

Gnomad4 AMR exome AF: 0.000854

Gnomad4 ASJ exome AF: 0.000206

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00452

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00148

Gnomad4 OTH exome AF: 0.000468

GnomAD4 genome AF: 0.00125 AC: 190 AN: 152358 Hom.: 1 Cov.: 34 AF XY: 0.00114 AC XY: 85 AN XY: 74512

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00210

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00180 Hom.: 0

Bravo AF: 0.00106

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	4.0
Dann	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs530536156; hg19: chr16-89984433;