rs121913558

Positions:

• chr18-60372178-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_005912.3(MC4R):​c.172A>T​(p.Ser58Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,890 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MC4R NM_005912.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.20

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925
• PP5: Variant 18-60372178-T-A is Pathogenic according to our data. Variant chr18-60372178-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 14321.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr18-60372178-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MC4R	NM_005912.3	c.172A>T	p.Ser58Cys	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.172A>T	p.Ser58Cys	missense_variant	1/1	6	NM_005912.3	ENSP00000299766.3
ENSG00000285681	ENST00000650201.1	n.113+42833T>A		intron_variant
ENSG00000285681	ENST00000658928.1	n.156+42833T>A		intron_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727248

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2001

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.77		Loss of helix (P = 0.1299);
MVP		0.84
MPC		0.10
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.79
gMVP		0.79

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: rs121913558; hg19: chr18-58039411;