18-60372045-A-G

Position:

• chr18-60372045-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PS1_Moderate PM1 PM5 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 nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. 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

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 Pathogenic. Variant got 10 ACMG points.

• PS1: Transcript NM_005912.3 (MC4R) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a helix (size 28) in uniprot entity MC4R_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_005912.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-60372045-A-C is described in Lovd as [Pathogenic].
• 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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MC4R	NM_005912.3	c.305T>C	p.Ile102Thr	missense_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.305T>C	p.Ile102Thr	missense_variant	1/1	6	NM_005912.3	ENSP00000299766.3
ENSG00000285681	ENST00000650201.1	n.113+42700A>G		intron_variant
ENSG00000285681	ENST00000658928.1	n.156+42700A>G		intron_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251448 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135896

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 SAS 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

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000570 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

MC4R-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 25, 2024

The MC4R c.305T>C variant is predicted to result in the amino acid substitution p.Ile102Thr. This variant was originally reported in a study of MC4R-related obesity (Lubrano-Berthelier et al 2003. PubMed ID: 12851297). Multiple functional studies indicated that this missense change showed impaired ligand binding (Tao. 2005 et al. PubMed ID: 16030156; He et al. 2014. PubMed ID: 25332687) and reduced basal activity relative to wild-type (Lubrano-Berthelier et al. 2006. PubMed ID: 16507637). An alternative missense change at the same amino acid position (Ile102Ser) was also documented in multiple individuals with obesity (Dubern et al. 2001. PubMed ID: 11487744). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

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
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs121913559; hg19: chr18-58039278;