NM_005912.3:c.305T>C

Variant names:

• chr18-60372045-A-G
• rs121913559
• NM_005912.3:c.305T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PM1 PM5 PP2 PP3_Strong PP5 BS2_Supporting

The NM_005912.3(MC4R):​c.305T>C​(p.Ile102Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I102S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: MC4R NM_005912.3 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.31
• Publications: 24 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 9 ACMG points.

• PM1: In a helix (size 28) in uniprot entity MC4R_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_005912.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-60372045-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 14322.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: -1.0099 (below the threshold of 3.09). Trascript score misZ: 0.30396 (below the threshold of 3.09). GenCC associations: The gene is linked to obesity due to melanocortin 4 receptor deficiency, inherited obesity.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant 18-60372045-A-G is Pathogenic according to our data. Variant chr18-60372045-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2634476.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAdExome4 at 15 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.305T>C	p.Ile102Thr	missense	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.305T>C	p.Ile102Thr	missense	Exon 1 of 1	ENSP00000299766.3	P32245
	ENSG00000285681	ENST00000650201.1		n.113+42700A>G		intron	N/A
	ENSG00000285681	ENST00000658928.1		n.156+42700A>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251448 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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 727246

African (AFR) AF: 0.0000299 AC: 1 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: 53418

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

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000552 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	MC4R-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		9.3
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.072	T
Polyphen		1.0	D
Vest4		0.96
MutPred		0.91		Gain of disorder (P = 0.0227)
MVP		0.79
MPC		0.045
ClinPred		0.96	D
GERP RS		5.9
Varity_R		0.52
gMVP		0.75
Mutation Taster		=7/93	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121913559; hg19: chr18-58039278;