chr18-60371827-C-T
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1BP4_StrongBS2
The NM_005912.3(MC4R):c.523G>A(p.Ala175Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000277 in 1,613,960 control chromosomes in the GnomAD database, including 3 homozygotes. 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
Consequence
NM_005912.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MC4R | NM_005912.3 | c.523G>A | p.Ala175Thr | missense_variant | 1/1 | ENST00000299766.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MC4R | ENST00000299766.5 | c.523G>A | p.Ala175Thr | missense_variant | 1/1 | NM_005912.3 | P1 | ||
ENST00000658928.1 | n.156+42482C>T | intron_variant, non_coding_transcript_variant | |||||||
ENST00000650201.1 | n.113+42482C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.000296 AC: 45AN: 152112Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000541 AC: 136AN: 251340Hom.: 0 AF XY: 0.000515 AC XY: 70AN XY: 135848
GnomAD4 exome AF: 0.000275 AC: 402AN: 1461848Hom.: 2 Cov.: 32 AF XY: 0.000279 AC XY: 203AN XY: 727236
GnomAD4 genome AF: 0.000296 AC: 45AN: 152112Hom.: 1 Cov.: 32 AF XY: 0.000310 AC XY: 23AN XY: 74294
ClinVar
Submissions by phenotype
BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20 Pathogenic:1Uncertain:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 20, 2003 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 04, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Mar 15, 2022 | - - |
Obesity Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Mar 16, 2011 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
MC4R-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 30, 2024 | The MC4R c.523G>A variant is predicted to result in the amino acid substitution p.Ala175Thr. This variant was previously reported in affected members of a family with severe familial obesity (Yeo et al. 2003. PubMed ID: 12588803) and in an apparently unrelated proband with severe obesity (Alfieri et al. 2010. PubMed ID: 20214954). However, this variant was also reported in unaffected control cohorts (Carlton et al. 2009. PubMed ID: 19091795) and has a minor allele frequency of up to ~1.0% in sub-populations in one large population database, including 1 homozygote. In vitro studies regarding the resulting function of the p.Ala175Thr variant protein are conflicting, with some authors reporting a mild reduction in activity or expression, and others reporting no change from wild type (Yeo et al. 2003. PubMed ID: 12588803; Farooqi et al. 2003. PubMed ID: 12646665; Mühlhaus et al. 2012. PubMed ID: 22688572; Lotta LA et al 2019. PubMed ID: 31002796). At this time, the clinical significance of this variant is classified as uncertain due to the absence of conclusive functional and genetic evidence. - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Sep 19, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at