18-60372527-T-G

Variant names:

• chr18-60372527-T-G
• rs34114122
• NM_005912.3:c.-178A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005912.3(MC4R):​c.-178A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0258 in 676,096 control chromosomes in the GnomAD database, including 565 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.044 (318 hom., cov: 32)
  • Exomes 𝑓: 0.021 (247 hom.)
• Consequence: MC4R NM_005912.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.138
• Publications: 14 publications found

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

ENSG00000285681 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MC4R	NM_005912.3	c.-178A>C		5_prime_UTR_variant	Exon 1 of 1	ENST00000299766.5	NP_005903.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MC4R	ENST00000299766.5	c.-178A>C		5_prime_UTR_variant	Exon 1 of 1	6	NM_005912.3	ENSP00000299766.3
ENSG00000285681	ENST00000650201.1	n.113+43182T>G		intron_variant	Intron 1 of 3
ENSG00000285681	ENST00000658928.1	n.156+43182T>G		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes AF: 0.0436 AC: 6640 AN: 152222 Hom.: 316 Cov.: 32

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0206

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.0323

Gnomad SAS AF: 0.0395

Gnomad FIN AF: 0.00357

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0133

Gnomad OTH AF: 0.0344

GnomAD4 exome AF: 0.0207 AC: 10816 AN: 523756 Hom.: 247 Cov.: 5 AF XY: 0.0207 AC XY: 5781 AN XY: 279692

African (AFR) AF: 0.121 AC: 1723 AN: 14184

American (AMR) AF: 0.0162 AC: 446 AN: 27538

Ashkenazi Jewish (ASJ) AF: 0.00459 AC: 75 AN: 16340

East Asian (EAS) AF: 0.0460 AC: 1452 AN: 31534

South Asian (SAS) AF: 0.0377 AC: 2005 AN: 53194

European-Finnish (FIN) AF: 0.00449 AC: 204 AN: 45396

Middle Eastern (MID) AF: 0.0139 AC: 30 AN: 2158

European-Non Finnish (NFE) AF: 0.0139 AC: 4227 AN: 304928

Other (OTH) AF: 0.0230 AC: 654 AN: 28484

GnomAD4 genome AF: 0.0436 AC: 6646 AN: 152340 Hom.: 318 Cov.: 32 AF XY: 0.0422 AC XY: 3145 AN XY: 74502

African (AFR) AF: 0.119 AC: 4942 AN: 41568

American (AMR) AF: 0.0206 AC: 315 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3470

East Asian (EAS) AF: 0.0322 AC: 167 AN: 5188

South Asian (SAS) AF: 0.0389 AC: 188 AN: 4832

European-Finnish (FIN) AF: 0.00357 AC: 38 AN: 10630

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0133 AC: 907 AN: 68026

Other (OTH) AF: 0.0345 AC: 73 AN: 2116

Alfa AF: 0.0246 Hom.: 400

Bravo AF: 0.0475

Asia WGS AF: 0.0440 AC: 151 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Obesity Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.7
DANN	Benign	0.76
PhyloP100		-0.14
PromoterAI		-0.0040	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs34114122; hg19: chr18-58039760;