chr16-89920158-C-T

Variant names:

• chr16-89920158-C-T
• rs3212367
• NM_002386.4:c.900C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002386.4(MC1R):​c.900C>T​(p.Phe300Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00317 in 1,614,052 control chromosomes in the GnomAD database, including 164 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (92 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (72 hom.)
• Consequence: MC1R NM_002386.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.73
• Publications: 13 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 16-89920158-C-T is Benign according to our data. Variant chr16-89920158-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.73 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0583 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.900C>T	p.Phe300Phe	synonymous	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.900C>T	p.Phe300Phe	synonymous	Exon 1 of 1	ENSP00000451605.1	Q01726
	ENSG00000198211	ENST00000556922.1	TSL:2	c.900C>T	p.Phe300Phe	synonymous	Exon 1 of 5	ENSP00000451560.1	A0A0B4J269
	MC1R	ENST00000555427.1	TSL:5	c.900C>T	p.Phe300Phe	synonymous	Exon 3 of 4	ENSP00000451760.1	G3V4F0

Frequencies

GnomAD3 genomes AF: 0.0174 AC: 2646 AN: 152254 Hom.: 92 Cov.: 33

Gnomad AFR AF: 0.0603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00733

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00434 AC: 1082 AN: 249048 AF XY: 0.00328

Gnomad AFR exome AF: 0.0605

Gnomad AMR exome AF: 0.00336

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.00168 AC: 2462 AN: 1461680 Hom.: 72 Cov.: 34 AF XY: 0.00141 AC XY: 1023 AN XY: 727126

African (AFR) AF: 0.0588 AC: 1967 AN: 33480

American (AMR) AF: 0.00376 AC: 168 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.0000666 AC: 74 AN: 1111866

Other (OTH) AF: 0.00393 AC: 237 AN: 60370

GnomAD4 genome AF: 0.0174 AC: 2652 AN: 152372 Hom.: 92 Cov.: 33 AF XY: 0.0171 AC XY: 1271 AN XY: 74512

African (AFR) AF: 0.0603 AC: 2506 AN: 41592

American (AMR) AF: 0.00732 AC: 112 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68044

Other (OTH) AF: 0.0109 AC: 23 AN: 2114

Alfa AF: 0.00830 Hom.: 20

Bravo AF: 0.0198

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Melanoma, cutaneous malignant, susceptibility to, 5 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	14
DANN	Benign	0.92
PhyloP100		1.7
Mutation Taster		=98/2	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: rs3212367; hg19: chr16-89986566;