Genetic Variant MC1R:p.Phe300Leu (chr16-89920156-TTC-CTA) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_002386.4(MC1R):c.898_900delTTCinsCTA (p.Phe300Leu) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. 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)

Consequence

MC1R
NM_002386.4 missense

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.02

Publications

0 publications found

Variant links:

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

MC1R links:

ENSG00000198211 (HGNC:):

ENSG00000198211 links:

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new If you want to explore the variant's impact on the transcript NM_002386.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Show applied only (1)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (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.898_900delTTCinsCTA p.Phe300Leu	missense	N/A	Prot: NP_002377.4

MC1R NM_002386.4

MANE Select

HGVSc / HGVSpc.898_900delTTCinsCTAp.Phe300Leu

Exon rankN/A

missense

Prot: NP_002377.4

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
MC1R ENST00000555147.2	TSL:6MANE Select	c.898_900delTTCinsCTA p.Phe300Leu	missense	N/A	Prot: ENSP00000451605.1 UniProt: Q01726
ENSG00000198211 ENST00000556922.1	TSL:2	c.898_900delTTCinsCTA p.Phe300Leu	missense	N/A	Prot: ENSP00000451560.1 UniProt: A0A0B4J269
MC1R ENST00000555427.1	TSL:5	c.898_900delTTCinsCTA p.Phe300Leu	missense	N/A	Prot: ENSP00000451760.1 UniProt: G3V4F0

MC1R ENST00000555147.2

TSL:6MANE Select

HGVSc / HGVSpc.898_900delTTCinsCTAp.Phe300Leu

Exon rankN/A

missense

Prot: ENSP00000451605.1UniProt: Q01726

ENSG00000198211 ENST00000556922.1

TSL:2

HGVSc / HGVSpc.898_900delTTCinsCTAp.Phe300Leu

Exon rankN/A

missense

Prot: ENSP00000451560.1UniProt: A0A0B4J269

MC1R ENST00000555427.1

TSL:5

HGVSc / HGVSpc.898_900delTTCinsCTAp.Phe300Leu

Exon rankN/A

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Uncertain	6.0

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence