rs151318945

Positions:

• chr16-89920206-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_002386.4(MC1R):​c.948C>T​(p.Ser316=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00232 in 1,612,908 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (6 hom.)
• Consequence: MC1R NM_002386.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.141

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 16-89920206-C-T is Benign according to our data. Variant chr16-89920206-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 321442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89920206-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.141 with no splicing effect.
• BS2: High AC in GnomAd4 at 332 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MC1R	NM_002386.4	c.948C>T	p.Ser316=	synonymous_variant	1/1	ENST00000555147.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MC1R	ENST00000555147.2	c.948C>T	p.Ser316=	synonymous_variant	1/1		NM_002386.4	P1
	ENST00000554623.1	n.606G>A		non_coding_transcript_exon_variant	2/2	3
MC1R	ENST00000555427.1	c.948C>T	p.Ser316=	splice_region_variant, synonymous_variant	3/4	5
MC1R	ENST00000639847.1	c.948C>T	p.Ser316=	synonymous_variant	3/3	5		P1

Frequencies

GnomAD3 genomes AF: 0.00218 AC: 332 AN: 152248 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00385

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00170 AC: 422 AN: 248552 Hom.: 1 AF XY: 0.00174 AC XY: 235 AN XY: 134968

Gnomad AFR exome AF: 0.000325

Gnomad AMR exome AF: 0.000667

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00307

Gnomad NFE exome AF: 0.00279

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00233 AC: 3410 AN: 1460542 Hom.: 6 Cov.: 34 AF XY: 0.00236 AC XY: 1717 AN XY: 726542

Gnomad4 AFR exome AF: 0.000389

Gnomad4 AMR exome AF: 0.000917

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00289

Gnomad4 NFE exome AF: 0.00279

Gnomad4 OTH exome AF: 0.00169

GnomAD4 genome AF: 0.00218 AC: 332 AN: 152366 Hom.: 1 Cov.: 33 AF XY: 0.00219 AC XY: 163 AN XY: 74512

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00358

Gnomad4 NFE AF: 0.00385

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00244 Hom.: 0

Bravo AF: 0.00168

EpiCase AF: 0.00207

EpiControl AF: 0.00214

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	MC1R: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	4.4
DANN	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs151318945; hg19: chr16-89986614;