rs34474212

Positions:

• chr16-89919505-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_002386.4(MC1R):​c.247T>C​(p.Ser83Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000542 in 1,613,152 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00053 (3 hom.)
• Consequence: MC1R NM_002386.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 2.63

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009303957).
• BP6: Variant 16-89919505-T-C is Benign according to our data. Variant chr16-89919505-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 321422.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=3}.
• BS2: High AC in GnomAd4 at 100 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MC1R	NM_002386.4	c.247T>C	p.Ser83Pro	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.247T>C	p.Ser83Pro	missense_variant	1/1		NM_002386.4	ENSP00000451605	P1
MC1R	ENST00000555427.1	c.247T>C	p.Ser83Pro	missense_variant	3/4	5		ENSP00000451760
MC1R	ENST00000639847.1	c.247T>C	p.Ser83Pro	missense_variant	3/3	5		ENSP00000492011	P1

Frequencies

GnomAD3 genomes AF: 0.000657 AC: 100 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00101 AC: 250 AN: 248738 Hom.: 2 AF XY: 0.00103 AC XY: 139 AN XY: 135032

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.0121

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000409

Gnomad OTH exome AF: 0.00248

GnomAD4 exome AF: 0.000530 AC: 774 AN: 1460832 Hom.: 3 Cov.: 31 AF XY: 0.000550 AC XY: 400 AN XY: 726660

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00170

Gnomad4 ASJ exome AF: 0.0128

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000246

Gnomad4 OTH exome AF: 0.00129

GnomAD4 genome AF: 0.000657 AC: 100 AN: 152320 Hom.: 0 Cov.: 33 AF XY: 0.000779 AC XY: 58 AN XY: 74476

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.0107

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00132 Hom.: 1

Bravo AF: 0.000733

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000766 AC: 93

EpiCase AF: 0.000763

EpiControl AF: 0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	MC1R: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 18, 2024	Identified in either the homozygous state or with a second MC1R variant in an individual with pale skin and red hair, however, additional clinical and segregation information were not provided (PMID: 11933208); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 30531825, 35452484, 23647022, 38565069, 11933208, 19656326, 24335900) -

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Skin/hair/eye pigmentation, variation in, 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Institute of Human Genetics, University Hospital of Duesseldorf

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	.;D;D;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.55	T;.;T;T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.0093	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Pathogenic	3.9	.;H;H;.
MutationTaster	Benign	0.99	D;D
PROVEAN	Uncertain	-3.3	D;.;D;N
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	D;.;D;D
Sift4G	Uncertain	0.012	D;.;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.85
MVP		0.82
MPC		0.13
ClinPred		0.18	T
GERP RS		4.9
Varity_R		0.95
gMVP		0.79

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: rs34474212; hg19: chr16-89985913;