chr16-89919033-A-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 18 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]

ENSG00000198211 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002386.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MC1R	NM_002386.4	MANE Select	c.-226A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 1	NP_002377.4
	MC1R	NM_002386.4	MANE Select	c.-226A>T		5_prime_UTR	Exon 1 of 1	NP_002377.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MC1R	ENST00000555147.2	TSL:6 MANE Select	c.-226A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 1	ENSP00000451605.1	Q01726
	MC1R	ENST00000555147.2	TSL:6 MANE Select	c.-226A>T		5_prime_UTR	Exon 1 of 1	ENSP00000451605.1	Q01726
	MC1R	ENST00000555427.1	TSL:5	c.-226A>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 4	ENSP00000451760.1	G3V4F0

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

African (AFR) AF: 0.501 AC: 5932 AN: 11850

American (AMR) AF: 0.495 AC: 7807 AN: 15784

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 3101 AN: 12778

East Asian (EAS) AF: 0.745 AC: 21808 AN: 29272

South Asian (SAS) AF: 0.538 AC: 18415 AN: 34222

European-Finnish (FIN) AF: 0.409 AC: 11192 AN: 27372

Middle Eastern (MID) AF: 0.316 AC: 572 AN: 1808

European-Non Finnish (NFE) AF: 0.252 AC: 61020 AN: 242346

Other (OTH) AF: 0.322 AC: 7666 AN: 23816

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

African (AFR) AF: 0.501 AC: 20752 AN: 41426

American (AMR) AF: 0.429 AC: 6561 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.245 AC: 850 AN: 3466

East Asian (EAS) AF: 0.644 AC: 3297 AN: 5116

South Asian (SAS) AF: 0.553 AC: 2663 AN: 4818

European-Finnish (FIN) AF: 0.413 AC: 4365 AN: 10562

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.255 AC: 17301 AN: 67890

Other (OTH) AF: 0.337 AC: 710 AN: 2106

Alfa AF: 0.309 Hom.: 1191

Bravo AF: 0.380

Asia WGS AF: 0.557 AC: 1940 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Melanoma, cutaneous malignant, susceptibility to, 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.85
DANN	Benign	0.56
PhyloP100		-1.6
PromoterAI		0.0010	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs3212363; hg19: chr16-89985441;