NM_002386.4:c.464T>C

Variant names:

• chr16-89919722-T-C
• rs1110400
• NM_002386.4:c.464T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 4P and 9B. PS3 BP4_Strong BP6 BS2

The NM_002386.4(MC1R):​c.464T>C​(p.Ile155Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0094 in 1,606,272 control chromosomes in the GnomAD database, including 102 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000322071: Functional studies demonstrate that I155T reduces cell surface expression of the MC1R protein and results in loss of cAMP signaling (Beaumont et al., 2007).". Synonymous variant affecting the same amino acid position (i.e. I155I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0066 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0097 (99 hom.)
• Consequence: MC1R NM_002386.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:6
• Conservation: PhyloP100: 5.05
• Publications: 145 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: Likely_benign. The variant received -5 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000322071: Functional studies demonstrate that I155T reduces cell surface expression of the MC1R protein and results in loss of cAMP signaling (Beaumont et al., 2007).
• BP4: Computational evidence support a benign effect (MetaRNN=0.0065425932).
• BP6: Variant 16-89919722-T-C is Benign according to our data. Variant chr16-89919722-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 239154.
• BS2: High AC in GnomAd4 at 1008 AD gene.

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.464T>C	p.Ile155Thr	missense	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.464T>C	p.Ile155Thr	missense	Exon 1 of 1	ENSP00000451605.1	Q01726
	ENSG00000198211	ENST00000556922.1	TSL:2	c.464T>C	p.Ile155Thr	missense	Exon 1 of 5	ENSP00000451560.1	A0A0B4J269
	MC1R	ENST00000555427.1	TSL:5	c.464T>C	p.Ile155Thr	missense	Exon 3 of 4	ENSP00000451760.1	G3V4F0

Frequencies

GnomAD3 genomes AF: 0.00661 AC: 1007 AN: 152244 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00719

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00564 AC: 1366 AN: 242204 AF XY: 0.00564

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00409

Gnomad ASJ exome AF: 0.00860

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00188

Gnomad NFE exome AF: 0.00922

Gnomad OTH exome AF: 0.00616

GnomAD4 exome AF: 0.00969 AC: 14089 AN: 1453910 Hom.: 99 Cov.: 34 AF XY: 0.00935 AC XY: 6764 AN XY: 723646

African (AFR) AF: 0.00161 AC: 54 AN: 33474

American (AMR) AF: 0.00445 AC: 199 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00846 AC: 221 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000441 AC: 38 AN: 86236

European-Finnish (FIN) AF: 0.00253 AC: 116 AN: 45830

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0116 AC: 12866 AN: 1111768

Other (OTH) AF: 0.00978 AC: 590 AN: 60306

GnomAD4 genome AF: 0.00662 AC: 1008 AN: 152362 Hom.: 3 Cov.: 33 AF XY: 0.00553 AC XY: 412 AN XY: 74504

African (AFR) AF: 0.00231 AC: 96 AN: 41584

American (AMR) AF: 0.00718 AC: 110 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 37 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000827 AC: 4 AN: 4834

European-Finnish (FIN) AF: 0.00235 AC: 25 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0106 AC: 724 AN: 68034

Other (OTH) AF: 0.00569 AC: 12 AN: 2110

Alfa AF: 0.00818 Hom.: 6

Bravo AF: 0.00638

TwinsUK AF: 0.00944 AC: 35

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00296 AC: 13

ESP6500EA AF: 0.0105 AC: 90

ExAC AF: 0.00523 AC: 635

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0101

EpiControl AF: 0.00883

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	2	1	not provided (4)
-	-	2	Melanoma, cutaneous malignant, susceptibility to, 5 (2)
-	-	2	not specified (2)
-	-	1	Tyrosinase-positive oculocutaneous albinism;C1849452:SKIN/HAIR/EYE PIGMENTATION, VARIATION IN, 2;C2751295:Melanoma, cutaneous malignant, susceptibility to, 5;C2751296:Increased analgesia from kappa-opioid receptor agonist, female-specific (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0065	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		5.0
PROVEAN	Pathogenic	-4.6	D
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.71
MVP		0.74
MPC		0.10
ClinPred		0.054	T
GERP RS		4.8
Varity_R		0.78
gMVP		0.38
Mutation Taster		=50/50	disease causing (ClinVar)

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: rs1110400; hg19: chr16-89986130;