18-60371415-G-C

Position:

• chr18-60371415-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_005912.3(MC4R):​c.935C>G​(p.Thr312Ser) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MC4R NM_005912.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.19

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_005912.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.82

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MC4R	NM_005912.3	c.935C>G	p.Thr312Ser	missense_variant	1/1	ENST00000299766.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MC4R	ENST00000299766.5	c.935C>G	p.Thr312Ser	missense_variant	1/1		NM_005912.3	P1
	ENST00000658928.1	n.156+42070G>C		intron_variant, non_coding_transcript_variant
	ENST00000650201.1	n.113+42070G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.082	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.018	D
Polyphen		0.86	P
Vest4		0.71
MutPred		0.65		Gain of disorder (P = 0.0426);
MVP		0.91
MPC		0.098
ClinPred		0.98	D
GERP RS		6.1
Varity_R		0.39
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1157656544; hg19: chr18-58038648;