18-60371544-A-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PP3PP5BP4BS1_SupportingBS2_Supporting

The NM_005912.3(MC4R):c.806T>A(p.Ile269Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000192 in 1,614,220 control chromosomes in the GnomAD database, including 4 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 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 4 hom. )

Consequence

MC4R
NM_005912.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:6

Conservation

PhyloP100: 9.32

Variant links:

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]

MC4R links:

ENSG00000285681 (HGNC:):

ENSG00000285681 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, Cadd, Eigen, FATHMM_MKL, M_CAP, phyloP100way_vertebrate, PrimateAI, PROVEAN [when BayesDel_addAF, max_spliceai, MetaRNN, MutationAssessor, MutationTaster was below the threshold]

PP5

Variant 18-60371544-A-T is Pathogenic according to our data. Variant chr18-60371544-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36486.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=6, Pathogenic=3}.

BP4

Computational evidence support a benign effect (MetaRNN=0.05223468). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000201 (294/1461872) while in subpopulation AMR AF= 0.00648 (290/44724). AF 95% confidence interval is 0.00587. There are 4 homozygotes in gnomad4_exome. There are 118 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 16 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MC4R	NM_005912.3 link	c.806T>A	p.Ile269Asn	missense_variant	Exon 1 of 1	ENST00000299766.5	NP_005903.2	P32245

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MC4R	ENST00000299766.5 link	c.806T>A	p.Ile269Asn	missense_variant	Exon 1 of 1	6	NM_005912.3	ENSP00000299766.3	P32245
ENSG00000285681	ENST00000650201.1 link	n.113+42199A>T		intron_variant	Intron 1 of 3
ENSG00000285681	ENST00000658928.1 link	n.156+42199A>T		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000981

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00103

AC:

259

AN:

251352

Hom.:

AF XY:

0.000707

AC XY:

AN XY:

135836

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00746

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000201

AC:

294

AN:

1461872

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

118

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00648

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:

0.00

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000105

AC:

AN:

152348

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000980

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000450

ExAC

AF:

0.000807

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20

Pathogenic:2Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Apr 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Medicine Lab, University of California San Francisco	Aug 25, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 14, 2024	- -

not provided

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2025	This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 269 of the MC4R protein (p.Ile269Asn). This variant is present in population databases (rs79783591, gnomAD 0.7%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with obesity (PMID: 19091795, 19889825, 30811542, 31841602, 35562395). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36486). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MC4R protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects MC4R function (PMID: 22106157, 24276017, 25332687, 31002796). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 07, 2020	Although the frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene, this variant was shown to associate with obesity in Mexican children and adults (PMID:31841602, http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments showed reduced cell surface expression and ligand binding, as well as loss of signal transduction (PMID:18801902,24276017,31002796). Computational tools predict that this variant is damaging. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2024	Identified in multiple individuals with obesity but it is unknown whether these individuals were screened for variants in other genes associated with obesity (PMID: 18801902, 30811542, 35562395, 31841602); Reported as a founder variant for obesity among individuals of Mexican background (PMID: 31841602); Published functional studies demonstrate a damaging effect (PMID: 31002796); 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: 17628007, 19091795, 22106157, 31002796, 25332687, 33045043, 18801902, 30811542, 35562395, 31841602, 31118516, 33542413, 35460704) -

Obesity

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Ile269Asn variant in MC4R has been reported in 4 individuals with Obesity (PMID: 18801902, 19091795), and has been identified in 0.7309% (259/35438) of Latino chromosomes, including 5 homozygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs79783591). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported as a VUS, likely pathogenic variant, and a pathogenic variant in ClinVar (Variation ID: 36486). In vitro functional studies provide some evidence that the p.Ile269Asn variant may impact cell surface expression, protein folding, and receptor activation (PMID: 18801902, 19091795). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS3, PS4_Supporting (Richards 2015). -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	May 23, 2014	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 25, 2019	Variant summary: MC4R c.806T>A (p.Ile269Asn) results in a non-conservative amino acid change located in the GPCR, rhodopsin-like, 7TM domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00092 in 277298 control chromosomes, predominantly at a frequency of 0.0073 within the Latino subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 15 fold of the estimated maximal expected allele frequency for a pathogenic variant in MC4R causing Early Onset Obesity phenotype (0.0005), suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. However, c.806T>A has been reported in the literature in multiple individuals affected with Early Onset Obesity (Hohenadel_2014, Tan_2009). Furthermore, at-least two of these reports identified this variant in individuals of Hispanic/Latina ancestry who are enriched for this variant among the control cohorts. These reports do not provide unequivocal conclusions about association of the variant with Early Onset Obesity. Experimental evidence evaluating an impact on protein function demonstrated the variant to have a significantly different EC50 (the concentration of ligand needed to achieve 50% of maximum effect) than that of the wild type (WT) receptor (Thearle_2012, Calton_2009), reduced expression at the cell surface and decreased receptor binding (Hohenadel_2014, Tan_2009) while, it also exhibited defective ligand-stimulated response compared to WT and was determined to have biased signaling in the ERK1/2 pathway (He_2014). Studies were contradictory in terms of cyclic AMP response after agonist administration either detecting loss of function or no significant difference in function compared to WT (Hohenadel_2014, Tan_2009). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the possibility that this is likely to represent a benign variation cannot be excluded. Due to equivocal reports of functional relevance the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 14, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.73

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.48

MetaRNN

Benign

0.052

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.9

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-5.4

REVEL

Uncertain

0.49

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.97

MVP

0.79

MPC

0.096

ClinPred

0.12

GERP RS

5.8

Varity_R

0.89

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over