rs376670171

Positions:

• chr16-89919773-G-A
• chr16-89919773-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002386.4(MC1R):​c.515G>A​(p.Ser172Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MC1R NM_002386.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.07

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MC1R	NM_002386.4	c.515G>A	p.Ser172Asn	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.515G>A	p.Ser172Asn	missense_variant	1/1		NM_002386.4	ENSP00000451605	P1
MC1R	ENST00000555427.1	c.515G>A	p.Ser172Asn	missense_variant	3/4	5		ENSP00000451760
MC1R	ENST00000639847.1	c.515G>A	p.Ser172Asn	missense_variant	3/3	5		ENSP00000492011	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	.;T;T;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;.;D;D
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Pathogenic	4.0	.;H;H;.
MutationTaster	Benign	1.0	D;D
PROVEAN	Uncertain	-2.4	N;.;N;N
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Uncertain	0.060	T;.;D;D
Polyphen		0.99	.;D;D;.
Vest4		0.77
MutPred		0.77		Loss of glycosylation at S172 (P = 0.0252);Loss of glycosylation at S172 (P = 0.0252);Loss of glycosylation at S172 (P = 0.0252);Loss of glycosylation at S172 (P = 0.0252);
MVP		0.79
MPC		0.11
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.85
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: rs376670171; hg19: chr16-89986181;