18-60372527-T-G

Position:

• chr18-60372527-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_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. Variant has been reported in ClinVar as Benign (★★).

• 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

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]

ENSG00000285681 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 18-60372527-T-G is Benign according to our data. Variant chr18-60372527-T-G is described in ClinVar as [Benign]. Clinvar id is 327719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-60372527-T-G is described in Lovd as [Likely_benign].
• 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/exons	MANE	Protein	UniProt
MC4R	NM_005912.3	c.-178A>C		5_prime_UTR_variant	1/1	ENST00000299766.5	NP_005903.2

Ensembl

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

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

Gnomad4 AFR exome AF: 0.121

Gnomad4 AMR exome AF: 0.0162

Gnomad4 ASJ exome AF: 0.00459

Gnomad4 EAS exome AF: 0.0460

Gnomad4 SAS exome AF: 0.0377

Gnomad4 FIN exome AF: 0.00449

Gnomad4 NFE exome AF: 0.0139

Gnomad4 OTH exome AF: 0.0230

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

Gnomad4 AFR AF: 0.119

Gnomad4 AMR AF: 0.0206

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.0322

Gnomad4 SAS AF: 0.0389

Gnomad4 FIN AF: 0.00357

Gnomad4 NFE AF: 0.0133

Gnomad4 OTH AF: 0.0345

Alfa AF: 0.0210 Hom.: 133

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.7
DANN	Benign	0.76

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: rs34114122; hg19: chr18-58039760;