18-60372240-T-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_ModerateBP6BS2_Supporting

The NM_005912.3(MC4R):​c.110A>T​(p.Asp37Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000669 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

MC4R
NM_005912.3 missense

Scores

1
18

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:5O:1

Conservation

PhyloP100: 4.10
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.14122966).
BP6
Variant 18-60372240-T-A is Benign according to our data. Variant chr18-60372240-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14319.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2, not_provided=1}. Variant chr18-60372240-T-A is described in Lovd as [Likely_benign].
BS2
High AC in GnomAd4 at 18 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
MC4RNM_005912.3 linkc.110A>T p.Asp37Val missense_variant Exon 1 of 1 ENST00000299766.5 NP_005903.2 P32245

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MC4RENST00000299766.5 linkc.110A>T p.Asp37Val missense_variant Exon 1 of 1 6 NM_005912.3 ENSP00000299766.3 P32245
ENSG00000285681ENST00000650201.1 linkn.113+42895T>A intron_variant Intron 1 of 3
ENSG00000285681ENST00000658928.1 linkn.156+42895T>A intron_variant Intron 1 of 3

Frequencies

GnomAD3 genomes
AF:
0.000118
AC:
18
AN:
152174
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.000265
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000676
AC:
17
AN:
251354
Hom.:
0
AF XY:
0.0000515
AC XY:
7
AN XY:
135834
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
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:
0.000141
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000616
AC:
90
AN:
1461888
Hom.:
0
Cov.:
32
AF XY:
0.0000564
AC XY:
41
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
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:
0.0000755
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.000118
AC:
18
AN:
152174
Hom.:
0
Cov.:
32
AF XY:
0.000108
AC XY:
8
AN XY:
74340
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000265
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000100
Hom.:
0
Bravo
AF:
0.0000831
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.0000494
AC:
6
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:5Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Obesity Uncertain:2Benign:1Other:1
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Nov 22, 2017
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

present with c.105C>A in two patients, phase not known -

Oct 02, 2015
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: not provided
Review Status: no classification provided
Collection Method: clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Uncertain:1Benign:2
-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dec 16, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 37 of the MC4R protein (p.Asp37Val). This variant is present in population databases (rs13447325, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features associated with MC4R-related obesity (PMID: 12970296). ClinVar contains an entry for this variant (Variation ID: 14319). 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 have shown that this missense change does not substantially affect MC4R function (PMID: 16752916). 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. -

-
Clinical Genetics, Academic Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not specified Benign:1
May 27, 2016
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20 Benign:1
Jan 01, 2019
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.087
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.43
CADD
Benign
20
DANN
Benign
0.97
DEOGEN2
Benign
0.28
T
Eigen
Benign
-0.28
Eigen_PC
Benign
-0.13
FATHMM_MKL
Uncertain
0.79
D
LIST_S2
Benign
0.81
T
M_CAP
Benign
0.018
T
MetaRNN
Benign
0.14
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.0
N
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-0.38
N
REVEL
Benign
0.062
Sift
Benign
0.088
T
Sift4G
Benign
0.25
T
Polyphen
0.0040
B
Vest4
0.29
MVP
0.67
MPC
0.015
ClinPred
0.064
T
GERP RS
4.4
Varity_R
0.10
gMVP
0.73

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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.

Other links and lift over

dbSNP: rs13447325; hg19: chr18-58039473; API