18-60371538-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_005912.3(MC4R):c.812G>A(p.Cys271Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C271R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: MC4R NM_005912.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.91

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_005912.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-60371539-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 18-60371538-C-T is Pathogenic according to our data. Variant chr18-60371538-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 14329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MC4R	NM_005912.3	c.812G>A	p.Cys271Tyr	missense_variant	1/1	ENST00000299766.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MC4R	ENST00000299766.5	c.812G>A	p.Cys271Tyr	missense_variant	1/1		NM_005912.3	P1
	ENST00000658928.1	n.156+42193C>T		intron_variant, non_coding_transcript_variant
	ENST00000650201.1	n.113+42193C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 727236

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000307 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Obesity Pathogenic:3

Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Dec 10, 2015	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 23, 2020	The p.Cys271Tyr variant in MC4R has been reported in at least 7 individuals with obesity, segregated with disease in these 7 affected relatives from 1 family (PMID: 12646665), and was absent from large population studies. This variant has also been reported in ClinVar as pathogenic (Variation ID: 14329). In vitro functional studies provide some evidence that the p.Cys271Tyr variant may impact protein function (PMID: 12646665, 12588803). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Cys271Arg, has been reported in association with disease in the literature and in ClinVar, slightly supporting that a change at this position may not be tolerated (PMID: 14504270, 18559663, 12646665/Variation ID: 372803). In summary, this variant meets criteria to be classified as pathogenic for obesity in an autosomal dominant manner based on the functional evidence resulting in absence of normal MC4R function and the demonstration of the variant cosegregating with disease in a large family. ACMG/AMP Criteria applied: PS3, PP1_strong, PM2, PP3, PM5_supporting (Richards 2015). -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Dec 19, 2013	- -

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

Mar 01, 2022

proposed classification - variant undergoing re-assessment, contact laboratory -

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
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.96		Loss of glycosylation at S270 (P = 0.0843);
MVP		0.89
MPC		0.11
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.95
gMVP		0.97

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: rs121913562; hg19: chr18-58038771;