rs121913560

chr18-60371842-T-Cchr18-60371842-T-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1 BP4_Moderate BS2

The NM_005912.3(MC4R):c.508A>G(p.Ile170Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,614,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000096 (0 hom.)
• Consequence: MC4R NM_005912.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:3
• Conservation: PhyloP100: 1.40

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_benign. Variant got -4 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, 3 uncertain in NM_005912.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.23309362).
• BS2: High AC in GnomAd at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MC4R	NM_005912.3	c.508A>G	p.Ile170Val	missense_variant	1/1	ENST00000299766.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MC4R	ENST00000299766.5	c.508A>G	p.Ile170Val	missense_variant	1/1		NM_005912.3	P1
	ENST00000658928.1	n.156+42497T>C		intron_variant, non_coding_transcript_variant
	ENST00000650201.1	n.113+42497T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000796 AC: 20 AN: 251336 Hom.: 0 AF XY: 0.0000663 AC XY: 9 AN XY: 135846

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000965 AC: 141 AN: 1461868 Hom.: 0 Cov.: 32 AF XY: 0.0000880 AC XY: 64 AN XY: 727236

Gnomad4 AFR exome AF: 0.00149

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000495

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74432

Gnomad4 AFR AF: 0.000554

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000120 Hom.: 0

Bravo AF: 0.000238

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000115 AC: 14

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20 Pathogenic:3 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Imperial College London Diabetes Centre, Mubadala Healthcare	May 01, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 11, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2001	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 170 of the MC4R protein (p.Ile170Val). This variant is present in population databases (rs121913560, gnomAD 0.05%). This missense change has been observed in individual(s) with clinical features of MC4R-related obesity (PMID: 10903341, 11487744, 18559663, 19011902, 26788538, 31751304, 31980526). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14323). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MC4R protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MC4R function (PMID: 10903341, 12690102, 12959994, 16752916, 19011902, 25332687, 29736023). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

MC4R-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 21, 2023

The MC4R c.508A>G variant is predicted to result in the amino acid substitution p.Ile170Val. This variant has been reported in several individuals with severe obesity; however, its role in pathogenesis has been controversial. It was originally described in two apparently unrelated patients with a BMI >30, and was found to marginally compromise receptor surface localization and function in vitro (Vaisse et al. 2000. PubMed ID: 10903341; Lubrano-Berthelier. 2006. PubMed ID: 16507637). Since then a significant number of studies have shown that it imparts no change to cell surface expression, ligand binding, or cAMP signaling (See for example, He. 2014. PubMed ID: 25332687; Clément et al. 2018. PubMed ID: 29736023, Supp Table 5). It was found to be a common variant among South African individuals with obesity (2%; n=9;); however, a match control cohort was not included (Logan. 2016. PubMed ID: 26788538). This variant is reported in 0.048% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org). Taken together, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.80	N
REVEL	Uncertain	0.40
Sift	Uncertain	0.012	D
Sift4G	Benign	0.16	T
Polyphen		0.81	P
Vest4		0.73
MVP		0.64
MPC		0.016
ClinPred		0.060	T
GERP RS		3.4
Varity_R		0.28
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121913560; hg19: chr18-58039075;