rs530536156

Variant names:

• chr16-89918025-C-T
• rs530536156
• ENST00000555427.1:c.-431C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The ENST00000555427.1(MC1R):​c.-431C>T variant causes a 5 prime UTR premature start codon gain 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. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0010 (0 hom.)
• Consequence: MC1R ENST00000555427.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.84
• Publications: 0 publications found

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]

LOC124903759 (HGNC:):

ACMG classification

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

• 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.
• BS2: High AC in GnomAd4 at 190 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC124903759	XM_047435031.1	c.1190C>T	p.Thr397Met	missense_variant	Exon 3 of 4		XP_047290987.1
LOC124903759	XM_047435032.1	c.*180C>T		3_prime_UTR_variant	Exon 3 of 3		XP_047290988.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MC1R	ENST00000555427.1	c.-431C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 4	5		ENSP00000451760.1
MC1R	ENST00000639847.1	c.-431C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 3	5		ENSP00000492011.1
ENSG00000267048	ENST00000570217.1	n.351C>T		non_coding_transcript_exon_variant	Exon 3 of 3	4

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

African (AFR) AF: 0.000283 AC: 1 AN: 3532

American (AMR) AF: 0.000854 AC: 2 AN: 2342

Ashkenazi Jewish (ASJ) AF: 0.000206 AC: 1 AN: 4866

East Asian (EAS) AF: 0.00 AC: 0 AN: 10954

South Asian (SAS) AF: 0.00452 AC: 3 AN: 664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 68

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 462

European-Non Finnish (NFE) AF: 0.00148 AC: 70 AN: 47302

Other (OTH) AF: 0.000468 AC: 3 AN: 6410

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

African (AFR) AF: 0.000433 AC: 18 AN: 41582

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00497 AC: 24 AN: 4826

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00210 AC: 143 AN: 68036

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs530536156; hg19: chr16-89984433;