rs17773630

Variant names:

• chr18-60371227-A-G
• rs17773630
• NM_005912.3:c.*124T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_005912.3(MC4R):​c.*124T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00676 in 1,008,936 control chromosomes in the GnomAD database, including 48 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 0.0049 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (44 hom.)
• Consequence: MC4R NM_005912.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.49
• Publications: 2 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=-0.81).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00495 (754/152326) while in subpopulation SAS AF = 0.0153 (74/4828). AF 95% confidence interval is 0.0125. There are 4 homozygotes in GnomAd4. There are 368 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 754 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005912.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MC4R	NM_005912.3	MANE Select	c.*124T>C		3_prime_UTR	Exon 1 of 1	NP_005903.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MC4R	ENST00000299766.5	TSL:6 MANE Select	c.*124T>C		3_prime_UTR	Exon 1 of 1	ENSP00000299766.3
	ENSG00000285681	ENST00000650201.1		n.113+41882A>G		intron	N/A
	ENSG00000285681	ENST00000658928.1		n.156+41882A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00496 AC: 755 AN: 152208 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0153

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00808

Gnomad OTH AF: 0.00526

GnomAD4 exome AF: 0.00708 AC: 6062 AN: 856610 Hom.: 44 Cov.: 11 AF XY: 0.00752 AC XY: 3362 AN XY: 446922

African (AFR) AF: 0.00175 AC: 38 AN: 21718

American (AMR) AF: 0.00236 AC: 95 AN: 40238

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 25 AN: 21684

East Asian (EAS) AF: 0.0000545 AC: 2 AN: 36702

South Asian (SAS) AF: 0.0161 AC: 1140 AN: 70852

European-Finnish (FIN) AF: 0.00123 AC: 49 AN: 39808

Middle Eastern (MID) AF: 0.0101 AC: 47 AN: 4632

European-Non Finnish (NFE) AF: 0.00763 AC: 4427 AN: 580300

Other (OTH) AF: 0.00588 AC: 239 AN: 40676

GnomAD4 genome AF: 0.00495 AC: 754 AN: 152326 Hom.: 4 Cov.: 32 AF XY: 0.00494 AC XY: 368 AN XY: 74486

African (AFR) AF: 0.00171 AC: 71 AN: 41570

American (AMR) AF: 0.00196 AC: 30 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.0153 AC: 74 AN: 4828

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10606

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00808 AC: 550 AN: 68032

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00431 Hom.: 0

Bravo AF: 0.00458

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.6
DANN	Benign	0.65
PhyloP100		1.5

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: rs17773630; hg19: chr18-58038460;