chr16-89918167-G-A

Variant names:

• chr16-89918167-G-A
• rs58664942
• ENST00000570217.1:n.493G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000570217.1(ENSG00000267048):​n.493G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00341 in 230,514 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0047 (3 hom., cov: 34)
  • Exomes 𝑓: 0.00087 (1 hom.)
• Consequence: ENSG00000267048 ENST00000570217.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.96
• Publications: 2 publications found

Genes affected

ENSG00000267048 (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

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 16-89918167-G-A is Benign according to our data. Variant chr16-89918167-G-A is described in ClinVar as [Benign]. Clinvar id is 887813.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00471 (717/152338) while in subpopulation AFR AF = 0.0165 (686/41574). AF 95% confidence interval is 0.0155. There are 3 homozygotes in GnomAd4. There are 333 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC124903759	XM_047435031.1	c.1212+120G>A		intron_variant	Intron 3 of 3		XP_047290987.1
LOC124903759	XM_047435032.1	c.*322G>A		downstream_gene_variant			XP_047290988.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000267048	ENST00000570217.1	n.493G>A		non_coding_transcript_exon_variant	Exon 3 of 3	4
MC1R	ENST00000555427.1	c.-409+120G>A		intron_variant	Intron 2 of 3	5		ENSP00000451760.1
MC1R	ENST00000639847.1	c.-409+120G>A		intron_variant	Intron 2 of 2	5		ENSP00000492011.1

Frequencies

GnomAD3 genomes AF: 0.00471 AC: 717 AN: 152220 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.0165

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.000870 AC: 68 AN: 78176 Hom.: 1 Cov.: 0 AF XY: 0.000860 AC XY: 31 AN XY: 36050

African (AFR) AF: 0.0153 AC: 56 AN: 3664

American (AMR) AF: 0.00206 AC: 5 AN: 2422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4934

East Asian (EAS) AF: 0.00 AC: 0 AN: 11120

South Asian (SAS) AF: 0.00 AC: 0 AN: 672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 64

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 476

European-Non Finnish (NFE) AF: 0.0000207 AC: 1 AN: 48314

Other (OTH) AF: 0.000922 AC: 6 AN: 6510

GnomAD4 genome AF: 0.00471 AC: 717 AN: 152338 Hom.: 3 Cov.: 34 AF XY: 0.00447 AC XY: 333 AN XY: 74488

African (AFR) AF: 0.0165 AC: 686 AN: 41574

American (AMR) AF: 0.00144 AC: 22 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00360 Hom.: 1

Bravo AF: 0.00524

Asia WGS AF: 0.00173 AC: 6 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 13, 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	-0.80
CADD	Benign	1.9
DANN	Benign	0.88
PhyloP100		-2.0

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

Other links and lift over

dbSNP: rs58664942; hg19: chr16-89984575;