rs138281308

Positions:

chr18-60371744-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_005912.3(MC4R):c.606C>A(p.Phe202Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0005 in 1,614,186 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 0.0028 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 2 hom. )

Consequence

MC4R
NM_005912.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 3.60

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009358466).

BP6

Variant 18-60371744-G-T is Benign according to our data. Variant chr18-60371744-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36484.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=3, Uncertain_significance=1}. Variant chr18-60371744-G-T is described in Lovd as [Likely_benign]. Variant chr18-60371744-G-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00278 (424/152306) while in subpopulation AFR AF= 0.00979 (407/41574). AF 95% confidence interval is 0.009. There are 2 homozygotes in gnomad4. There are 200 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 424 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MC4R	NM_005912.3 linkuse as main transcript	c.606C>A	p.Phe202Leu	missense_variant	1/1	ENST00000299766.5	NP_005903.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	Appris
MC4R	ENST00000299766.5 linkuse as main transcript	c.606C>A	p.Phe202Leu	missense_variant	1/1	NM_005912.3	ENSP00000299766	P1
	ENST00000658928.1 linkuse as main transcript	n.156+42399G>T		intron_variant, non_coding_transcript_variant
	ENST00000650201.1 linkuse as main transcript	n.113+42399G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00280

AC:

426

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00984

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000692

AC:

174

AN:

251324

Hom.:

AF XY:

0.000493

AC XY:

AN XY:

135824

show subpopulations

Gnomad AFR exome

AF:

0.00954

Gnomad AMR exome

AF:

0.000463

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:

0.000489

GnomAD4 exome

AF:

0.000262

AC:

383

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000252

AC XY:

183

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00989

Gnomad4 AMR exome

AF:

0.000425

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:

0.00000450

Gnomad4 OTH exome

AF:

0.000447

GnomAD4 genome

AF:

0.00278

AC:

424

AN:

152306

Hom.:

Cov.:

AF XY:

0.00269

AC XY:

200

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00979

Gnomad4 AMR

AF:

0.000850

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:

0.00142

Alfa

AF:

0.000477

Hom.:

Bravo

AF:

0.00332

ESP6500AA

AF:

0.00794

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000848

AC:

103

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Obesity

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 07, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Inherited obesity

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

Aug 22, 2023

- -

Monogenic diabetes

Benign:1

Likely benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Dec 07, 2018

ACMG criteria: BP4 (REVEL 0.120 + 8 predictors; not using PP3 predictors) + BS2 (29 cases + 27 controls in T2Dgenes): likely benign -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 29, 2023

- -

MC4R-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 19, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

Eigen

Benign

-0.19

Eigen_PC

Benign

0.019

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.79

MetaRNN

Benign

0.0094

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.2

REVEL

Benign

0.12

Sift

Benign

0.38

Sift4G

Benign

0.62

Polyphen

0.060

Vest4

0.22

MutPred

0.89

Gain of helix (P = 0.2059);

MVP

0.60

MPC

0.014

ClinPred

0.018

GERP RS

5.0

Varity_R

0.34

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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