rs3212362

Variant names:

• chr16-89918936-G-A
• rs3212362
• NM_002386.4:c.-323G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-89918936-G-A
• chr16-89918936-G-C

Variant summary

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

The NM_002386.4(MC1R):​c.-323G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 413,372 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0020 (9 hom., cov: 33)
  • Exomes 𝑓: 0.00061 (3 hom.)
• Consequence: MC1R NM_002386.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.775
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 16-89918936-G-A is Benign according to our data. Variant chr16-89918936-G-A is described in ClinVar as Benign. ClinVar VariationId is 321408.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00197 (300/152348) while in subpopulation AMR AF = 0.0186 (285/15302). AF 95% confidence interval is 0.0168. There are 9 homozygotes in GnomAd4. There are 180 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 300 AD gene.

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.-323G>A		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.-323G>A		5_prime_UTR	Exon 1 of 1	ENSP00000451605.1
	MC1R	ENST00000555427.1	TSL:5	c.-323G>A		5_prime_UTR	Exon 3 of 4	ENSP00000451760.1
	MC1R	ENST00000639847.1	TSL:5	c.-323G>A		5_prime_UTR	Exon 3 of 3	ENSP00000492011.1

Frequencies

GnomAD3 genomes AF: 0.00198 AC: 302 AN: 152230 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0188

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000955

GnomAD4 exome AF: 0.000605 AC: 158 AN: 261024 Hom.: 3 Cov.: 0 AF XY: 0.000636 AC XY: 84 AN XY: 132026

African (AFR) AF: 0.000303 AC: 3 AN: 9890

American (AMR) AF: 0.0113 AC: 111 AN: 9854

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9518

East Asian (EAS) AF: 0.0000487 AC: 1 AN: 20520

South Asian (SAS) AF: 0.0000476 AC: 1 AN: 21016

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13854

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1274

European-Non Finnish (NFE) AF: 0.000183 AC: 29 AN: 158274

Other (OTH) AF: 0.000773 AC: 13 AN: 16824

GnomAD4 genome AF: 0.00197 AC: 300 AN: 152348 Hom.: 9 Cov.: 33 AF XY: 0.00242 AC XY: 180 AN XY: 74498

African (AFR) AF: 0.0000721 AC: 3 AN: 41590

American (AMR) AF: 0.0186 AC: 285 AN: 15302

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68028

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

Alfa AF: 0.000106 Hom.: 0

Bravo AF: 0.00236

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Melanoma, cutaneous malignant, susceptibility to, 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	5.0
DANN	Benign	0.81
PhyloP100		-0.78
PromoterAI		-0.062	Neutral

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: rs3212362; hg19: chr16-89985344;