rs121913564
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PP3_ModeratePP5_Very_Strong
The NM_005912.3(MC4R):āc.947T>Gā(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 (ā ā ).
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 32)
Exomes š: 0.000016 ( 0 hom. )
Consequence
MC4R
NM_005912.3 missense
NM_005912.3 missense
Scores
8
9
2
Clinical Significance
Conservation
PhyloP100: 8.95
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM1
?
In a topological_domain Cytoplasmic (size 27) in uniprot entity MC4R_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_005912.3
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. Variant chr18-60371403-A-C is described in Lovd as [Pathogenic]. Variant chr18-60371403-A-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MC4R | NM_005912.3 | c.947T>G | p.Ile316Ser | missense_variant | 1/1 | ENST00000299766.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MC4R | ENST00000299766.5 | c.947T>G | p.Ile316Ser | missense_variant | 1/1 | NM_005912.3 | P1 | ||
ENST00000658928.1 | n.156+42058A>C | intron_variant, non_coding_transcript_variant | |||||||
ENST00000650201.1 | n.113+42058A>C | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152190Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251428Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135886
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GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461882Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14AN XY: 727242
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152190Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74366
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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
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 23, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 20, 2003 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 17, 2021 | - - |
Obesity due to melanocortin 4 receptor deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 24, 2022 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Obesity Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Gain of disorder (P = 0.0157);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at