NM_005912.3:c.305T>G

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_005912.3(MC4R):​c.305T>G​(p.Ile102Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I102T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MC4R NM_005912.3 missense
• Clinical Significance: 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: Pathogenic. The variant received 12 ACMG points.

• PM1: In a helix (size 28) in uniprot entity MC4R_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_005912.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• 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, 0.981
• PP5: Variant 18-60372045-A-C is Pathogenic according to our data. 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.

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.305T>G	p.Ile102Ser	missense	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.305T>G	p.Ile102Ser	missense	Exon 1 of 1	ENSP00000299766.3
	ENSG00000285681	ENST00000650201.1		n.113+42700A>C		intron	N/A
	ENSG00000285681	ENST00000658928.1		n.156+42700A>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000110 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20 Pathogenic:1

Oct 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		9.3
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.027	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.91		Gain of disorder (P = 0.0022)
MVP		0.82
MPC		0.073
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.60
gMVP		0.90
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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;