rs764575014

Variant names:

• chr18-60371365-A-C
• NM_005912.3:c.985T>G

Your query was ambiguous. Multiple possible variants found:

• chr18-60371365-A-C
• chr18-60371365-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1 PM2 BP4_Moderate BS2_Supporting

The NM_005912.3(MC4R):​c.985T>G​(p.Ser329Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: MC4R NM_005912.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.11

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 1 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 27) in uniprot entity MC4R_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_005912.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10578722).
• BS2: High AC in GnomAdExome4 at 5 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 rank	MANE	Protein	UniProt
MC4R	NM_005912.3	c.985T>G	p.Ser329Ala	missense_variant	Exon 1 of 1	ENST00000299766.5	NP_005903.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MC4R	ENST00000299766.5	c.985T>G	p.Ser329Ala	missense_variant	Exon 1 of 1	6	NM_005912.3	ENSP00000299766.3
ENSG00000285681	ENST00000650201.1	n.113+42020A>C		intron_variant	Intron 1 of 3
ENSG00000285681	ENST00000658928.1	n.156+42020A>C		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461862 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000612 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	12
DANN	Benign	0.39
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.072
Sift	Benign	0.090	T
Sift4G	Benign	0.15	T
Polyphen		0.0	B
Vest4		0.044
MVP		0.65
MPC		0.013
ClinPred		0.063	T
GERP RS		0.17
Varity_R		0.070
gMVP		0.80

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-58038598;