16-89919033-A-T

Variant names:

• chr16-89919033-A-T
• rs3212363
• NM_002386.4:c.-226A>T

Variant summary

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

The NM_002386.4(MC1R):​c.-226A>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 0.353 in 551,120 control chromosomes in the GnomAD database, including 40,709 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (11869 hom., cov: 32)
  • Exomes 𝑓: 0.34 (28840 hom.)
• Consequence: MC1R NM_002386.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.62

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]

ENSG00000198211 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 16-89919033-A-T is Benign according to our data. Variant chr16-89919033-A-T is described in ClinVar as [Benign]. Clinvar id is 321411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.626 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MC1R	NM_002386.4	c.-226A>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 1	ENST00000555147.2	NP_002377.4
MC1R	NM_002386.4	c.-226A>T		5_prime_UTR_variant	Exon 1 of 1	ENST00000555147.2	NP_002377.4
LOC124903759	XM_047435031.1	c.*78A>T		downstream_gene_variant			XP_047290987.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MC1R	ENST00000555147	c.-226A>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 1		NM_002386.4	ENSP00000451605.1
MC1R	ENST00000555147	c.-226A>T		5_prime_UTR_variant	Exon 1 of 1		NM_002386.4	ENSP00000451605.1
ENSG00000198211	ENST00000556922.1	c.-226A>T		upstream_gene_variant		2		ENSP00000451560.1

Frequencies

GnomAD3 genomes AF: 0.374 AC: 56724 AN: 151758 Hom.: 11834 Cov.: 32

Gnomad AFR AF: 0.500

Gnomad AMI AF: 0.243

Gnomad AMR AF: 0.428

Gnomad ASJ AF: 0.245

Gnomad EAS AF: 0.645

Gnomad SAS AF: 0.555

Gnomad FIN AF: 0.413

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.333

GnomAD4 exome AF: 0.344 AC: 137513 AN: 399248 Hom.: 28840 Cov.: 0 AF XY: 0.350 AC XY: 72405 AN XY: 206856

Gnomad4 AFR exome AF: 0.501

Gnomad4 AMR exome AF: 0.495

Gnomad4 ASJ exome AF: 0.243

Gnomad4 EAS exome AF: 0.745

Gnomad4 SAS exome AF: 0.538

Gnomad4 FIN exome AF: 0.409

Gnomad4 NFE exome AF: 0.252

Gnomad4 OTH exome AF: 0.322

GnomAD4 genome AF: 0.374 AC: 56811 AN: 151872 Hom.: 11869 Cov.: 32 AF XY: 0.387 AC XY: 28754 AN XY: 74238

Gnomad4 AFR AF: 0.501

Gnomad4 AMR AF: 0.429

Gnomad4 ASJ AF: 0.245

Gnomad4 EAS AF: 0.644

Gnomad4 SAS AF: 0.553

Gnomad4 FIN AF: 0.413

Gnomad4 NFE AF: 0.255

Gnomad4 OTH AF: 0.337

Alfa AF: 0.309 Hom.: 1191

Bravo AF: 0.380

Asia WGS AF: 0.557 AC: 1940 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 22, 2018

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	-0.84
CADD	Benign	0.85
DANN	Benign	0.56

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

Publications

LitVar

Other links and lift over

dbSNP: rs3212363; hg19: chr16-89985441;