NM_001138.2:c.199G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001138.2(AGRP):c.199G>A(p.Ala67Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0372 in 1,614,120 control chromosomes in the GnomAD database, including 1,313 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.029 ( 81 hom., cov: 32)

Exomes 𝑓: 0.038 ( 1232 hom. )

Consequence

AGRP
NM_001138.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:2O:1

Conservation

PhyloP100: 0.943

Publications

57 publications found

Variant links:

Genes affected

AGRP (HGNC:330): (agouti related neuropeptide) This gene encodes an antagonist of the melanocortin-3 and melanocortin-4 receptor. It appears to regulate hypothalamic control of feeding behavior via melanocortin receptor and/or intracellular calcium regulation, and thus plays a role in weight homeostasis. Mutations in this gene have been associated with late on-set obesity. [provided by RefSeq, Dec 2009]

AGRP links:

ATP6V0D1-DT (HGNC:55268): (ATP6V0D1 divergent transcript)

ATP6V0D1-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025504827).

BP6

Variant 16-67483042-C-T is Benign according to our data. Variant chr16-67483042-C-T is described in ClinVar as [Benign]. Clinvar id is 7329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0881 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRP	NM_001138.2 link	c.199G>A	p.Ala67Thr	missense_variant	Exon 3 of 4	ENST00000290953.3	NP_001129.1	O00253C6SUN5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGRP	ENST00000290953.3 link	c.199G>A	p.Ala67Thr	missense_variant	Exon 3 of 4	1	NM_001138.2	ENSP00000290953.3		O00253

Frequencies

GnomAD3 genomes

AF:

0.0293

AC:

4452

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00939

Gnomad AMI

AF:

0.0592

Gnomad AMR

AF:

0.0297

Gnomad ASJ

AF:

0.0571

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00931

Gnomad FIN

AF:

0.0374

Gnomad MID

AF:

0.146

Gnomad NFE

AF:

0.0407

Gnomad OTH

AF:

0.0454

GnomAD2 exomes

AF:

0.0315

AC:

7923

AN:

251442

AF XY:

0.0322

show subpopulations

Gnomad AFR exome

AF:

0.00874

Gnomad AMR exome

AF:

0.0238

Gnomad ASJ exome

AF:

0.0603

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0379

Gnomad NFE exome

AF:

0.0434

Gnomad OTH exome

AF:

0.0417

GnomAD4 exome

AF:

0.0381

AC:

55641

AN:

1461808

Hom.:

1232

Cov.:

AF XY:

0.0374

AC XY:

27221

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.0109

AC:

366

AN:

33478

American (AMR)

AF:

0.0242

AC:

1084

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0619

AC:

1617

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0116

AC:

999

AN:

86258

European-Finnish (FIN)

AF:

0.0416

AC:

2222

AN:

53414

Middle Eastern (MID)

AF:

0.0947

AC:

546

AN:

5766

European-Non Finnish (NFE)

AF:

0.0417

AC:

46324

AN:

1111940

Other (OTH)

AF:

0.0411

AC:

2481

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

2932

5864

8795

11727

14659

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0292

AC:

4451

AN:

152312

Hom.:

Cov.:

AF XY:

0.0280

AC XY:

2088

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00943

AC:

392

AN:

41562

American (AMR)

AF:

0.0297

AC:

455

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.0571

AC:

198

AN:

3468

East Asian (EAS)

AF:

0.000579

AC:

AN:

5184

South Asian (SAS)

AF:

0.00931

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0374

AC:

397

AN:

10622

Middle Eastern (MID)

AF:

0.136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0408

AC:

2772

AN:

68010

Other (OTH)

AF:

0.0449

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

208

416

623

831

1039

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0376

Hom.:

439

Bravo

AF:

0.0277

TwinsUK

AF:

0.0461

AC:

171

ALSPAC

AF:

0.0420

AC:

162

ESP6500AA

AF:

0.00955

AC:

ESP6500EA

AF:

0.0408

AC:

351

ExAC

AF:

0.0316

AC:

3842

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.0429

EpiControl

AF:

0.0468

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Leanness, inherited

Pathogenic:1

Apr 30, 2004

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Inherited obesity

Benign:1

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

AGRP-related condition

Benign:1

Jan 25, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Obesity, late-onset

Other:1

Aug 30, 2019

OMIM

Significance:association

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.68

MetaRNN

Benign

0.0026

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.6

PhyloP100

0.94

PrimateAI

Benign

0.44

PROVEAN

Benign

0.19

REVEL

Benign

0.030

Sift

Benign

1.0

Sift4G

Benign

0.81

Polyphen

0.074

Vest4

0.045

MPC

1.1

ClinPred

0.025

GERP RS

2.5

Varity_R

0.080

gMVP

0.27

Mutation Taster

=86/14

disease causing (ClinVar)

(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

Publications

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NM_001138.2:c.199G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over