rs52820871

Variant names:

Germline classification Cancer classification (beta)

Variant summary

Our verdict is . The variant received -10 ACMG points: 0P and 10B. BS2BP4_ModerateBP6_Strong

The NM_005912.3(MC4R):c.751A>C (p.Ile251Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0107 (AC=17,294) in the gnomAD database across 1,614,030 control chromosomes, including 123 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.0129. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.I251T: Uncertain_significance (ClinVar VariationId 3357414, 0 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

Frequency

Genomes: 𝑓 0.0074 ( 6 hom., cov: 32)

Exomes 𝑓: 0.011 ( 117 hom. )

Consequence

MC4R
NM_005912.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:13

Conservation

PhyloP100: 6.70

Publications

101 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, SD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia

MC4R links:

ENSG00000285681 (HGNC:):

ENSG00000285681 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_005912.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

BP6

ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).

BS2

≥2 homozygotes in gnomAD — observed in healthy adults (BS2); GnomAD homozygous count = 123.; Very high cumulative gnomAD AC = 17294 (any 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.751A>C	p.Ile251Leu	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.751A>C	p.Ile251Leu	missense	Exon 1 of 1	ENSP00000299766.3	P32245
ENSG00000285681	ENST00000650201.1		n.113+42254T>G		intron	N/A
ENSG00000285681	ENST00000658928.1		n.156+42254T>G		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00740

AC:

1126

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00726

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.0113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0114

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.00692

AC:

1740

AN:

251350

AF XY:

0.00704

show subpopulations

Gnomad AFR exome

AF:

0.00191

Gnomad AMR exome

AF:

0.00402

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0101

Gnomad NFE exome

AF:

0.0110

Gnomad OTH exome

AF:

0.00554

GnomAD4 exome

AF:

0.0111

AC:

16168

AN:

1461792

Hom.:

117

Cov.:

AF XY:

0.0107

AC XY:

7775

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

33480

American (AMR)

AF:

0.00398

AC:

178

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

26102

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00203

AC:

175

AN:

86258

European-Finnish (FIN)

AF:

0.0105

AC:

560

AN:

53420

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0131

AC:

14571

AN:

1111948

Other (OTH)

AF:

0.00979

AC:

591

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

1013

2026

3039

4052

5065

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

558

1116

1674

2232

2790

<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:

0.00740

AC:

1126

AN:

152238

Hom.:

Cov.:

AF XY:

0.00720

AC XY:

536

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.00243

AC:

101

AN:

41548

American (AMR)

AF:

0.00725

AC:

111

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000830

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0113

AC:

120

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0114

AC:

773

AN:

68004

Other (OTH)

AF:

0.00615

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

110

164

219

274

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00982

Hom.:

Bravo

AF:

0.00628

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0106

EpiControl

AF:

0.0106

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.0000160

AC:

AN:

122812

Turkish Variome

AF:

0.00194

AC:

AN:

6712

Hom.:

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.000112

AC:

AN:

8960

Hom.:

ABraOM SABE-WGS-1171

AF:

0.00512

AC:

AN:

2342

Hom.:

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (3)

Obesity (3)

BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20 (1)

MC4R-related disorder (1)

Monogenic diabetes (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.17

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-2.0

PhyloP100

6.7

PrimateAI

Uncertain

0.74

PROVEAN

Benign

1.8

REVEL

Benign

0.14

Sift

Benign

1.0

Sift4G

Benign

1.0

Varity_R

0.14

gMVP

0.90

Mutation Taster

=91/9

polymorphism

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over