rs121913563

chr18-60371827-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BP4_Strong BS2

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:
  • Genomes: 𝑓 0.00030 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (2 hom.)
• Consequence: MC4R NM_005912.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:5 B:1
• Conservation: PhyloP100: 3.28

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_005912.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.008500457).
• BS2: High AC in GnomAd at 45 AD gene.

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: 45 AN: 152112 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000541 AC: 136 AN: 251340 Hom.: 0 AF XY: 0.000515 AC XY: 70 AN XY: 135848

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.0102

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000275 AC: 402 AN: 1461848 Hom.: 2 Cov.: 32 AF XY: 0.000279 AC XY: 203 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.0110

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000432

Gnomad4 OTH exome AF: 0.000911

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152112 Hom.: 1 Cov.: 32 AF XY: 0.000310 AC XY: 23 AN XY: 74294

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00836

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000957

Alfa AF: 0.000637 Hom.: 0

Bravo AF: 0.000431

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000486 AC: 59

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20 Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Mar 15, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 04, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 20, 2003	- -

Obesity Pathogenic:1 Uncertain: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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	17
Dann	Benign	0.26
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.064
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.0085	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.19	N
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.38	N
REVEL	Benign	0.13
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.016	B
Vest4		0.14
MVP		0.53
MPC		0.016
ClinPred		0.033	T
GERP RS		5.0
Varity_R		0.42
gMVP		0.78

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

Other links and lift over

dbSNP: rs121913563; hg19: chr18-58039060;