chr18-60371403-A-C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 11P and 4B. PP2PP3_ModeratePP5_Very_StrongBS2

The NM_005912.3(MC4R):​c.947T>G​(p.Ile316Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

MC4R
NM_005912.3 missense

Scores

8
9
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 8.95

Publications

18 publications found
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 Gene-Disease associations (from GenCC):
  • inherited obesity
    Inheritance: AD Classification: STRONG Submitted by: Laboratory for Molecular Medicine
  • obesity due to melanocortin 4 receptor deficiency
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: -1.0099 (below the threshold of 3.09). Trascript score misZ: 0.30396 (below the threshold of 3.09). GenCC associations: The gene is linked to obesity due to melanocortin 4 receptor deficiency, inherited obesity.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.938
PP5
Variant 18-60371403-A-C is Pathogenic according to our data. Variant chr18-60371403-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MC4RNM_005912.3 linkc.947T>G p.Ile316Ser 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.947T>G p.Ile316Ser missense_variant Exon 1 of 1 6 NM_005912.3 ENSP00000299766.3 P32245
ENSG00000285681ENST00000650201.1 linkn.113+42058A>C intron_variant Intron 1 of 3
ENSG00000285681ENST00000658928.1 linkn.156+42058A>C intron_variant Intron 1 of 3

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152190
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:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000199
AC:
5
AN:
251428
AF XY:
0.0000294
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000157
AC:
23
AN:
1461882
Hom.:
0
Cov.:
31
AF XY:
0.0000193
AC XY:
14
AN XY:
727242
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.000255
AC:
22
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53414
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1112006
Other (OTH)
AF:
0.00
AC:
0
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.484
Heterozygous variant carriers
0
3
6
8
11
14
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152190
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74366
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41452
American (AMR)
AF:
0.00
AC:
0
AN:
15278
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5192
South Asian (SAS)
AF:
0.000414
AC:
2
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10618
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68026
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
ExAC
AF:
0.0000494
AC:
6

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20 Pathogenic:3
Nov 17, 2021
Fulgent Genetics, Fulgent Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Mar 20, 2003
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Dec 23, 2021
Revvity Omics, Revvity
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Obesity due to melanocortin 4 receptor deficiency Pathogenic:1
Feb 24, 2022
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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

Obesity Pathogenic:1
Apr 28, 2017
Illumina Laboratory Services, Illumina
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The MC4R c.947T>G (p.Ile316Ser) variant has been reported in three studies in which it is found in a total of eight obese individuals from three families (Farooqi et al. 2003; Saeed et al. 2012; Saeed et al. 2015). The variant was identified in a homozygous state in three affected individuals, including a sibling pair, from a consanguineous family and in another unrelated individual. Another family, in which the variant segregated with disease, included one affected homozygote and three affected heterozygotes who were less obese than the homozygote. The p.Ile316Ser variant was absent from 80 controls but is reported at a frequency of 0.00036 in the South Asian population of the Exome Aggregation Consortium. Functional studies conducted in cell lines demonstrated that the p.Ile316Ser variant results in partial loss of function and a 14-fold decrease in binding affinity for MSH analog as compared to wild type protein. Furthermore, the p.Ile316Ser protein was less abundant in the plasma membrane and localized in the endoplasmic reticulum as a ubiquitinated protein (Farooqi et al. 2003; Yeo et al. 2003; Granell et al. 2010). Based on the collective evidence, the p.Ile316Ser variant is classified as likely pathogenic for obesity. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.73
BayesDel_addAF
Uncertain
0.093
D
BayesDel_noAF
Pathogenic
0.16
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.73
D
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.95
D
M_CAP
Uncertain
0.16
D
MetaRNN
Pathogenic
0.94
D
MetaSVM
Benign
-0.63
T
MutationAssessor
Uncertain
2.4
M
PhyloP100
8.9
PrimateAI
Uncertain
0.65
T
PROVEAN
Uncertain
-3.8
D
REVEL
Pathogenic
0.67
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0030
D
Polyphen
0.99
D
Vest4
0.99
MutPred
0.78
Gain of disorder (P = 0.0157);
MVP
0.89
MPC
0.027
ClinPred
0.90
D
GERP RS
6.1
Varity_R
0.76
gMVP
0.97
Mutation Taster
=10/90
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121913564; hg19: chr18-58038636; API