rs35040147

Positions:

• chr16-89919755-C-A
• chr16-89919755-C-G
• chr16-89919755-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002386.4(MC1R):​c.497C>A​(p.Ala166Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,456,054 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A166G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MC1R NM_002386.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.638

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MC1R	NM_002386.4	c.497C>A	p.Ala166Glu	missense_variant	1/1	ENST00000555147.2	NP_002377.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MC1R	ENST00000555147.2	c.497C>A	p.Ala166Glu	missense_variant	1/1	6	NM_002386.4	ENSP00000451605.1
ENSG00000198211	ENST00000556922.1	c.497C>A	p.Ala166Glu	missense_variant	1/5	2		ENSP00000451560.1
MC1R	ENST00000555427.1	c.497C>A	p.Ala166Glu	missense_variant	3/4	5		ENSP00000451760.1
MC1R	ENST00000639847.1	c.497C>A	p.Ala166Glu	missense_variant	3/3	5		ENSP00000492011.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456054 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 724576

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Uncertain	0.69	.;D;D;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.27	N
LIST_S2	Uncertain	0.96	D;.;D;D
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.43	T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Pathogenic	3.8	.;H;H;.
PROVEAN	Uncertain	-3.1	D;.;D;N
REVEL	Benign	0.19
Sift	Uncertain	0.0010	D;.;D;D
Sift4G	Uncertain	0.017	D;.;D;D
Polyphen		0.94	.;P;P;.
Vest4		0.49
MutPred		0.64		Loss of MoRF binding (P = 0.0567);Loss of MoRF binding (P = 0.0567);Loss of MoRF binding (P = 0.0567);Loss of MoRF binding (P = 0.0567);
MVP		0.75
MPC		0.10
ClinPred		0.88	D
GERP RS		1.0
Varity_R		0.67
gMVP		0.58

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

Publications

LitVar

Other links and lift over

dbSNP: rs35040147; hg19: chr16-89986163;