16-89920158-C-G

Variant names:

• chr16-89920158-C-G
• rs3212367
• NM_002386.4:c.900C>G
• MC1R p.Phe300Leu

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_002386.4(MC1R):c.900C>G (p.Phe300Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000000684 (AC=1) in the gnomAD database across 1,461,682 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000000899. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.F300= (synonymous): Benign/Likely_benign (ClinVar VariationId 258654, 2 stars); p.F300V: Uncertain_significance (ClinVar VariationId 862255, 2 stars)

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MC1R NM_002386.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.73
• Publications: 8 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]

MC1R Gene-Disease associations (from GenCC):

• oculocutaneous albinism type 2

  Inheritance: AR Classification: MODERATE Submitted by: PanelApp Australia

ENSG00000198211 (HGNC:):

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000000899 — very rare for AD+AR gene (threshold 0.0001) — PM2 moderate.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MC1R NM_002386.4	MANE Select	c.900C>G p.Phe300Leu	missense	Exon 1 of 1	Prot: NP_002377.4

MC1R NM_002386.4

MANE Select

HGVSc / HGVSpc.900C>Gp.Phe300Leu

Exon rankExon 1 of 1

missense

Prot: NP_002377.4

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MC1R ENST00000555147.2	TSL:6MANE Select	c.900C>G p.Phe300Leu	missense	Exon 1 of 1	Prot: ENSP00000451605.1 UniProt:
	ENSG00000198211 ENST00000556922.1	TSL:2	c.900C>G p.Phe300Leu	missense	Exon 1 of 5	Prot: ENSP00000451560.1 UniProt:
	MC1R ENST00000555427.1	TSL:5	c.900C>G p.Phe300Leu	missense	Exon 3 of 4	Prot: ENSP00000451760.1 UniProt:

MC1R ENST00000555147.2

TSL:6MANE Select

HGVSc / HGVSpc.900C>Gp.Phe300Leu

Exon rankExon 1 of 1

missense

Prot: ENSP00000451605.1UniProt: Q01726

ENSG00000198211 ENST00000556922.1

TSL:2

HGVSc / HGVSpc.900C>Gp.Phe300Leu

Exon rankExon 1 of 5

missense

Prot: ENSP00000451560.1UniProt: A0A0B4J269

MC1R ENST00000555427.1

TSL:5

HGVSc / HGVSpc.900C>Gp.Phe300Leu

Exon rankExon 3 of 4

missense

Prot: ENSP00000451760.1UniProt: G3V4F0

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 exome	AF: 6.84e-7	AC:1	Hom:0	AN:1461682	Cov:34
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	24
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.90	D
FuncVEP CTI	Pathogenic	0.67
GPN-Star LLR	N/A	-4.0
GPN-Star score	N/A	4.0
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.032	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.6	L
PhyloP100	Benign	1.7
popEVE	Benign	-2.5
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.22	T
Varity_R	N/A	0.49
VESM-3B	Benign	-5.6

Showing 26 of 26 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs3212367;

hg19: chr16-89986566;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar