rs121917829

chr18-60371489-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_005912.3(MC4R):c.861T>A(p.Tyr287Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MC4R NM_005912.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.48

Genes affected

MC4R (HGNC:6932): (melanocortin 4 receptor) The protein encoded by this gene is a membrane-bound receptor and member of the melanocortin receptor family. The encoded protein interacts with adrenocorticotropic and MSH hormones and is mediated by G proteins. This is an intronless gene. Defects in this gene are a cause of autosomal dominant obesity. [provided by RefSeq, Jan 2010]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-60371489-A-T is Pathogenic according to our data. Variant chr18-60371489-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 14332.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MC4R	NM_005912.3	c.861T>A	p.Tyr287Ter	stop_gained	1/1	ENST00000299766.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MC4R	ENST00000299766.5	c.861T>A	p.Tyr287Ter	stop_gained	1/1		NM_005912.3	P1
	ENST00000658928.1	n.156+42144A>T		intron_variant, non_coding_transcript_variant
	ENST00000650201.1	n.113+42144A>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Obesity due to melanocortin 4 receptor deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 20, 2018

The p.Tyr287X variant in MC4R has been reported in at least 1 homozygous individual with obesity and segregated with disease in 2 heterozygous relatives (Farooqi 2003, Yeo 2003). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 287. The MC4R protein is encoded by a single exon; therefore, this alteration is more likely to escape nonsense mediated decay (NMD), resulting in a truncated protein that is missing one transmembrane domain and the c-terminal tail. The c-terminal tail contains a peptide signal which is required for targeting the MC4R protein to the plasma membrane, and removal of that peptide results in cytoplasmic retention of the MC4R protein (Ho 1999). In addition, in vitro studies found this variant resulted in a complete loss of protein activity and absent or reduced cell surface expression (Farooqi 2003, Yeo 2003, Xiang 2003). Haploinsufficiency of the MC4R gene is an established disease mechanism in MC4R-related obesity. In summary, this variant meets criteria to be classified as pathogenic for MC4R-related obesity in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1_Strong, PM2, PM1, PS3_Supporting, PM3_Supporting. -

BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 20, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	34
Dann	Uncertain	0.99
Eigen	Uncertain	0.39
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.84	D
MutationTaster	Benign	1.0	A
Vest4		0.86
GERP RS		-1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121917829; hg19: chr18-58038722;