dbSNP rs2229616: MC4R:p.Val103Ile (chr18-60372043-C-T) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_005912.3(MC4R):c.307G>A(p.Val103Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0182 in 1,614,174 control chromosomes in the GnomAD database, including 281 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 14 hom., cov: 32)

Exomes 𝑓: 0.018 ( 267 hom. )

Consequence

MC4R
NM_005912.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1U:1B:12

Conservation

PhyloP100: 6.14

Publications

198 publications found

Variant links:

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]

MC4R Gene-Disease associations (from GenCC):

inherited obesity
Inheritance: AD Classification: STRONG Submitted by: Laboratory for Molecular Medicine
obesity due to melanocortin 4 receptor deficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

MC4R links:

ENSG00000285681 (HGNC:):

ENSG00000285681 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_005912.3

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: -1.0099 (below the threshold of 3.09). Trascript score misZ: 0.30396 (below the threshold of 3.09). GenCC associations: The gene is linked to inherited obesity, obesity due to melanocortin 4 receptor deficiency.

BP4

Computational evidence support a benign effect (MetaRNN=0.0067133605).

BP6

Variant 18-60372043-C-T is Benign according to our data. Variant chr18-60372043-C-T is described in ClinVar as Benign. ClinVar VariationId is 218330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0154 (2350/152308) while in subpopulation SAS AF = 0.0243 (117/4816). AF 95% confidence interval is 0.0207. There are 14 homozygotes in GnomAd4. There are 1116 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2350 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005912.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MC4R	NM_005912.3	MANE Select	c.307G>A	p.Val103Ile	missense	Exon 1 of 1	NP_005903.2	P32245

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MC4R	ENST00000299766.5	TSL:6 MANE Select	c.307G>A	p.Val103Ile	missense	Exon 1 of 1	ENSP00000299766.3	P32245
ENSG00000285681	ENST00000650201.1		n.113+42698C>T		intron	N/A
ENSG00000285681	ENST00000658928.1		n.156+42698C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0154

AC:

2350

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0156

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00510

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.0200

Gnomad SAS

AF:

0.0251

Gnomad FIN

AF:

0.0120

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0182

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.0161

AC:

4057

AN:

251448

AF XY:

0.0167

show subpopulations

Gnomad AFR exome

AF:

0.0132

Gnomad AMR exome

AF:

0.00330

Gnomad ASJ exome

AF:

0.00387

Gnomad EAS exome

AF:

0.0216

Gnomad FIN exome

AF:

0.0116

Gnomad NFE exome

AF:

0.0200

Gnomad OTH exome

AF:

0.0129

GnomAD4 exome

AF:

0.0185

AC:

26996

AN:

1461866

Hom.:

267

Cov.:

AF XY:

0.0186

AC XY:

13508

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.0151

AC:

505

AN:

33480

American (AMR)

AF:

0.00353

AC:

158

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00459

AC:

120

AN:

26136

East Asian (EAS)

AF:

0.0157

AC:

623

AN:

39700

South Asian (SAS)

AF:

0.0212

AC:

1830

AN:

86258

European-Finnish (FIN)

AF:

0.0136

AC:

726

AN:

53418

Middle Eastern (MID)

AF:

0.0156

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0198

AC:

21966

AN:

1111986

Other (OTH)

AF:

0.0162

AC:

978

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

1686

3371

5057

6742

8428

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

844

1688

2532

3376

4220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0154

AC:

2350

AN:

152308

Hom.:

Cov.:

AF XY:

0.0150

AC XY:

1116

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0157

AC:

651

AN:

41566

American (AMR)

AF:

0.00510

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3470

East Asian (EAS)

AF:

0.0199

AC:

103

AN:

5186

South Asian (SAS)

AF:

0.0243

AC:

117

AN:

4816

European-Finnish (FIN)

AF:

0.0120

AC:

127

AN:

10626

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0182

AC:

1238

AN:

68024

Other (OTH)

AF:

0.0109

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

118

236

353

471

589

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0184

Hom.:

Bravo

AF:

0.0152

TwinsUK

AF:

0.0178

AC:

ALSPAC

AF:

0.0169

AC:

ESP6500AA

AF:

0.0179

AC:

ESP6500EA

AF:

0.0185

AC:

159

ExAC

AF:

0.0174

AC:

2116

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0164

EpiControl

AF:

0.0177

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20 (2)

not provided (2)

Obesity (3)

MC4R POLYMORPHISM (1)

MC4R-related disorder (1)

Monogenic diabetes (1)

OBESITY, RESISTANCE TO (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

Eigen

Benign

0.086

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.61

MetaRNN

Benign

0.0067

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PhyloP100

6.1

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.070

REVEL

Benign

0.050

Sift

Benign

0.25

Sift4G

Benign

0.63

Polyphen

0.025

Vest4

0.061

MPC

0.022

ClinPred

0.017

GERP RS

5.9

Varity_R

0.22

gMVP

0.63

Mutation Taster

=86/14

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over