chr16-89919510-C-A

Position:

• chr16-89919510-C-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM5 BP4_Strong BP6 BS2

The NM_002386.4(MC1R):​c.252C>A​(p.Asp84Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00948 in 1,613,160 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D84?) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0053 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0099 (98 hom.)
• Consequence: MC1R NM_002386.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5 O:1
• Conservation: PhyloP100: 5.00

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 Benign. Variant got -7 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-89919510-C-R is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.014244467).
• BP6: Variant 16-89919510-C-A is Benign according to our data. Variant chr16-89919510-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14309.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=3}. Variant chr16-89919510-C-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 811 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MC1R	NM_002386.4	c.252C>A	p.Asp84Glu	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.252C>A	p.Asp84Glu	missense_variant	1/1	6	NM_002386.4	ENSP00000451605.1
ENSG00000198211	ENST00000556922.1	c.252C>A	p.Asp84Glu	missense_variant	1/5	2		ENSP00000451560.1
MC1R	ENST00000555427.1	c.252C>A	p.Asp84Glu	missense_variant	3/4	5		ENSP00000451760.1
MC1R	ENST00000639847.1	c.252C>A	p.Asp84Glu	missense_variant	3/3	5		ENSP00000492011.1

Frequencies

GnomAD3 genomes AF: 0.00533 AC: 811 AN: 152256 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00205

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00980

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00524 AC: 1304 AN: 248704 Hom.: 7 AF XY: 0.00518 AC XY: 699 AN XY: 135010

Gnomad AFR exome AF: 0.00167

Gnomad AMR exome AF: 0.00206

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00177

Gnomad NFE exome AF: 0.00989

Gnomad OTH exome AF: 0.00595

GnomAD4 exome AF: 0.00992 AC: 14484 AN: 1460786 Hom.: 98 Cov.: 31 AF XY: 0.00955 AC XY: 6942 AN XY: 726628

Gnomad4 AFR exome AF: 0.00158

Gnomad4 AMR exome AF: 0.00224

Gnomad4 ASJ exome AF: 0.00180

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00199

Gnomad4 NFE exome AF: 0.0122

Gnomad4 OTH exome AF: 0.00936

GnomAD4 genome AF: 0.00532 AC: 811 AN: 152374 Hom.: 2 Cov.: 33 AF XY: 0.00486 AC XY: 362 AN XY: 74508

Gnomad4 AFR AF: 0.00204

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00235

Gnomad4 NFE AF: 0.00980

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00868 Hom.: 12

Bravo AF: 0.00555

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00183 AC: 8

ESP6500EA AF: 0.0100 AC: 86

ExAC AF: 0.00527 AC: 640

EpiCase AF: 0.0104

EpiControl AF: 0.00984

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	MC1R: PP3, BS2 -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MC1R p.Asp84Glu variant was identified in 15 of 302 proband chromosomes (frequency: 0.0497) from individuals or families with melanoma and was identified in 2 of 298 control chromosomes (frequency: 0.0067) from healthy individuals (Valverde_2016_PMDI:8894704; Matichard_2004_PMID:14757863). The D84E variant has also been associated with red hair and fair skin (Raimondi_2008_PMID:18366057; Beaumont_2007_PMID:17616515). The variant was identified in dbSNP (ID: rs1805006) and ClinVar (classified as benign by Invitae, likely benign by Illumina and likely pathogenic by GeneDx); the variant was not identified in Cosmic or LOVD 3.0. The variant was identified in control databases in 1440 of 280086 chromosomes (7 homozygous) at a frequency of 0.005141 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 1222 of 127966 chromosomes (freq: 0.009549), Other in 38 of 7140 chromosomes (freq: 0.005322), Latino in 71 of 35352 chromosomes (freq: 0.002008), Ashkenazi Jewish in 20 of 10324 chromosomes (freq: 0.001937), European (Finnish) in 47 of 24950 chromosomes (freq: 0.001884) and African in 42 of 24236 chromosomes (freq: 0.001733), while the variant was not observed in the East Asian or South Asian populations. In vitro expression studies revealed that the D84E variant has reduced cell surface expression and corresponding impairment in cAMP coupling which is associated with the red hair and fair skin pigmentation phenotype (Beaumont_2007_PMID: 17616515). The p.Asp84 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 11, 2022	PS3_supporting, PS4_moderate -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 2018	Reported previously in association with increased risk for UV exposure-related melanoma (Puig-Butille et al., 2013; Raimondi et al., 2008); Published functional studies demonstrate a damaging effect: reduced cell surface expression and decreased ability to elevate intracellular cAMP levels (Beaumont et al., 2007); This variant is associated with the following publications: (PMID: 23647022, 11875032, 18366057, 18657399, 22572819, 19924138, 8894704, 26103569, 19656326, 24335900, 17616515, 29405243, 27755135, 30872112, 29795986, 29898205, 30657907, 14757863, 29583157, 29316344, 25159867, 30531825, 31382929, 30414346, 14709592) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Melanoma, cutaneous malignant, susceptibility to, 5 Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
risk factor, no assertion criteria provided	literature only	OMIM	Oct 01, 1996	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	.;D;D;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.74	T;.;T;T
MetaRNN	Benign	0.014	T;T;T;T
MetaSVM	Uncertain	0.47	D
MutationAssessor	Pathogenic	3.6	.;H;H;.
PROVEAN	Uncertain	-3.7	D;.;D;N
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Pathogenic	0.0010	D;.;D;D
Polyphen		0.99	.;D;D;.
Vest4		0.97
MutPred		0.24		Gain of disorder (P = 0.336);Gain of disorder (P = 0.336);Gain of disorder (P = 0.336);Gain of disorder (P = 0.336);
MVP		0.94
MPC		0.11
ClinPred		0.069	T
GERP RS		2.9
Varity_R		0.91
gMVP		0.65

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: rs1805006; hg19: chr16-89985918;