chr16-89918196-T-C

Variant names:

• chr16-89918196-T-C
• rs3212357
• ENST00000570217.1:n.522T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000570217.1(ENSG00000267048):​n.522T>C 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 0.574 in 229,264 control chromosomes in the GnomAD database, including 42,573 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (30294 hom., cov: 33)
  • Exomes 𝑓: 0.53 (12279 hom.)
• Consequence: ENSG00000267048 ENST00000570217.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.36
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 16-89918196-T-C is Benign according to our data. Variant chr16-89918196-T-C is described in ClinVar as [Benign]. Clinvar id is 321389.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 rank	MANE	Protein	UniProt
LOC124903759	XM_047435031.1	c.1212+149T>C		intron_variant	Intron 3 of 3		XP_047290987.1
LOC124903759	XM_047435032.1	c.*351T>C		downstream_gene_variant			XP_047290988.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000267048	ENST00000570217.1	n.522T>C		non_coding_transcript_exon_variant	Exon 3 of 3	4
MC1R	ENST00000555427.1	c.-409+149T>C		intron_variant	Intron 2 of 3	5		ENSP00000451760.1
MC1R	ENST00000639847.1	c.-409+149T>C		intron_variant	Intron 2 of 2	5		ENSP00000492011.1

Frequencies

GnomAD3 genomes AF: 0.597 AC: 90748 AN: 151954 Hom.: 30231 Cov.: 33

Gnomad AFR AF: 0.875

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.587

Gnomad ASJ AF: 0.407

Gnomad EAS AF: 0.917

Gnomad SAS AF: 0.679

Gnomad FIN AF: 0.518

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.551

GnomAD4 exome AF: 0.528 AC: 40796 AN: 77192 Hom.: 12279 Cov.: 0 AF XY: 0.523 AC XY: 18632 AN XY: 35636

African (AFR) AF: 0.877 AC: 3191 AN: 3640

American (AMR) AF: 0.622 AC: 1487 AN: 2390

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 1978 AN: 4854

East Asian (EAS) AF: 0.915 AC: 10103 AN: 11042

South Asian (SAS) AF: 0.655 AC: 431 AN: 658

European-Finnish (FIN) AF: 0.569 AC: 33 AN: 58

Middle Eastern (MID) AF: 0.532 AC: 249 AN: 468

European-Non Finnish (NFE) AF: 0.420 AC: 20019 AN: 47654

Other (OTH) AF: 0.514 AC: 3305 AN: 6428

GnomAD4 genome AF: 0.598 AC: 90872 AN: 152072 Hom.: 30294 Cov.: 33 AF XY: 0.602 AC XY: 44778 AN XY: 74338

African (AFR) AF: 0.876 AC: 36373 AN: 41538

American (AMR) AF: 0.588 AC: 8992 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 1411 AN: 3464

East Asian (EAS) AF: 0.918 AC: 4731 AN: 5156

South Asian (SAS) AF: 0.678 AC: 3270 AN: 4826

European-Finnish (FIN) AF: 0.518 AC: 5476 AN: 10566

Middle Eastern (MID) AF: 0.595 AC: 175 AN: 294

European-Non Finnish (NFE) AF: 0.426 AC: 28948 AN: 67910

Other (OTH) AF: 0.554 AC: 1171 AN: 2114

Alfa AF: 0.438 Hom.: 2966

Bravo AF: 0.615

Asia WGS AF: 0.777 AC: 2704 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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	-0.88
CADD	Benign	4.9
DANN	Benign	0.64
PhyloP100		-2.4
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs3212357; hg19: chr16-89984604;