20-56248973-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_019888.3(MC3R):c.130G>A(p.Val44Ile) variant causes a missense change. The variant allele was found at a frequency of 0.114 in 1,613,936 control chromosomes in the GnomAD database, including 15,923 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.19 (4424 hom., cov: 32)
  • Exomes 𝑓: 0.11 (11499 hom.)
• Consequence: MC3R NM_019888.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.66

Genes affected

MC3R (HGNC:6931): (melanocortin 3 receptor) This gene encodes a G-protein-coupled receptor for melanocyte-stimulating hormone and adrenocorticotropic hormone that is expressed in tissues other than the adrenal cortex and melanocytes. This gene maps to the same region as the locus for benign neonatal epilepsy. Mice deficient for this gene have increased fat mass despite decreased food intake, suggesting a role for this gene product in the regulation of energy homeostasis. Mutations in this gene are associated with a susceptibility to obesity in humans. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050959885).
• BP6: Variant 20-56248973-G-A is Benign according to our data. Variant chr20-56248973-G-A is described in ClinVar as [Benign]. Clinvar id is 1227705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.418 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MC3R	NM_019888.3	c.130G>A	p.Val44Ile	missense_variant	1/1	ENST00000243911.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MC3R	ENST00000243911.2	c.130G>A	p.Val44Ile	missense_variant	1/1		NM_019888.3	P1

Frequencies

GnomAD3 genomes AF: 0.191 AC: 29030 AN: 151956 Hom.: 4404 Cov.: 32

Gnomad AFR AF: 0.423

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.0956

Gnomad EAS AF: 0.236

Gnomad SAS AF: 0.207

Gnomad FIN AF: 0.0924

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.0859

Gnomad OTH AF: 0.147

GnomAD3 exomes AF: 0.136 AC: 34155 AN: 250886 Hom.: 3579 AF XY: 0.134 AC XY: 18131 AN XY: 135602

Gnomad AFR exome AF: 0.432

Gnomad AMR exome AF: 0.0905

Gnomad ASJ exome AF: 0.0853

Gnomad EAS exome AF: 0.231

Gnomad SAS exome AF: 0.208

Gnomad FIN exome AF: 0.0909

Gnomad NFE exome AF: 0.0871

Gnomad OTH exome AF: 0.116

GnomAD4 exome AF: 0.106 AC: 154810 AN: 1461862 Hom.: 11499 Cov.: 34 AF XY: 0.108 AC XY: 78500 AN XY: 727232

Gnomad4 AFR exome AF: 0.434

Gnomad4 AMR exome AF: 0.0908

Gnomad4 ASJ exome AF: 0.0880

Gnomad4 EAS exome AF: 0.239

Gnomad4 SAS exome AF: 0.207

Gnomad4 FIN exome AF: 0.0949

Gnomad4 NFE exome AF: 0.0837

Gnomad4 OTH exome AF: 0.125

GnomAD4 genome AF: 0.191 AC: 29107 AN: 152074 Hom.: 4424 Cov.: 32 AF XY: 0.190 AC XY: 14110 AN XY: 74344

Gnomad4 AFR AF: 0.423

Gnomad4 AMR AF: 0.111

Gnomad4 ASJ AF: 0.0956

Gnomad4 EAS AF: 0.235

Gnomad4 SAS AF: 0.208

Gnomad4 FIN AF: 0.0924

Gnomad4 NFE AF: 0.0859

Gnomad4 OTH AF: 0.152

Alfa AF: 0.107 Hom.: 3419

Bravo AF: 0.201

TwinsUK AF: 0.0804 AC: 298

ALSPAC AF: 0.0848 AC: 327

ESP6500AA AF: 0.419 AC: 1845

ESP6500EA AF: 0.0865 AC: 744

ExAC AF: 0.145 AC: 17635

Asia WGS AF: 0.244 AC: 847 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 24, 2019	This variant is associated with the following publications: (PMID: 24487982, 26818770, 16123355) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.029	T
Eigen	Benign	0.048
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.83	L
MutationTaster	Benign	0.00082	P
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.089
Sift	Benign	0.049	D
Sift4G	Benign	0.19	T
Vest4		0.058
MPC		0.20
ClinPred		0.042	T
GERP RS		4.0
Varity_R		0.088
gMVP		0.55

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: rs3827103; hg19: chr20-54824029; COSMIC: COSV54763631;