18-60371513-GCA-GCACA

Variant names:

• chr18-60371513-G-GCA
• rs193922687
• NM_005912.3:c.835_836dupTG

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 12P and 4B. PVS1_Strong PP5_Very_Strong BS2

The NM_005912.3(MC4R):​c.835_836dupTG​(p.Phe280AlafsTer12) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000219 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. C279C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: MC4R NM_005912.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.91
• Publications: 7 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: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.
• PP5: Variant 18-60371513-G-GCA is Pathogenic according to our data. Variant chr18-60371513-G-GCA is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 36487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 32 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MC4R	NM_005912.3	MANE Select	c.835_836dupTG	p.Phe280AlafsTer12	frameshift	Exon 1 of 1	NP_005903.2	P32245

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MC4R	ENST00000299766.5	TSL:6 MANE Select	c.835_836dupTG	p.Phe280AlafsTer12	frameshift	Exon 1 of 1	ENSP00000299766.3	P32245
	ENSG00000285681	ENST00000650201.1		n.113+42175_113+42176dupCA		intron	N/A
	ENSG00000285681	ENST00000658928.1		n.156+42175_156+42176dupCA		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251368 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1111988

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Obesity (2)
1	-	-	BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20 (1)
1	-	-	MC4R-related disorder (1)
1	-	-	not provided (1)
1	-	-	Obesity due to melanocortin 4 receptor deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs193922687; hg19: chr18-58038746;