Genetic Variant AGRP:p.Glu41Glu (chr16-67483276-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001138.2(AGRP):c.123G>A(p.Glu41Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0548 in 1,585,708 control chromosomes in the GnomAD database, including 4,162 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 1366 hom., cov: 33)

Exomes 𝑓: 0.050 ( 2796 hom. )

Consequence

AGRP
NM_001138.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.464

Publications

16 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 16-67483276-C-T is Benign according to our data. Variant chr16-67483276-C-T is described in ClinVar as [Benign]. Clinvar id is 1280192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.464 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRP	NM_001138.2 link	c.123G>A	p.Glu41Glu	synonymous_variant	Exon 2 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.123G>A	p.Glu41Glu	synonymous_variant	Exon 2 of 4	1	NM_001138.2	ENSP00000290953.3		O00253

Frequencies

GnomAD3 genomes

AF:

0.100

AC:

15228

AN:

152122

Hom.:

1356

Cov.:

show subpopulations

Gnomad AFR

AF:

0.243

Gnomad AMI

AF:

0.0592

Gnomad AMR

AF:

0.0641

Gnomad ASJ

AF:

0.0579

Gnomad EAS

AF:

0.00385

Gnomad SAS

AF:

0.0726

Gnomad FIN

AF:

0.0374

Gnomad MID

AF:

0.174

Gnomad NFE

AF:

0.0426

Gnomad OTH

AF:

0.0957

GnomAD2 exomes

AF:

0.0582

AC:

12582

AN:

216048

AF XY:

0.0568

show subpopulations

Gnomad AFR exome

AF:

0.246

Gnomad AMR exome

AF:

0.0389

Gnomad ASJ exome

AF:

0.0611

Gnomad EAS exome

AF:

0.00256

Gnomad FIN exome

AF:

0.0378

Gnomad NFE exome

AF:

0.0441

Gnomad OTH exome

AF:

0.0549

GnomAD4 exome

AF:

0.0499

AC:

71557

AN:

1433470

Hom.:

2796

Cov.:

AF XY:

0.0500

AC XY:

35531

AN XY:

710872

show subpopulations

African (AFR)

AF:

0.256

AC:

8378

AN:

32674

American (AMR)

AF:

0.0412

AC:

1689

AN:

40956

Ashkenazi Jewish (ASJ)

AF:

0.0625

AC:

1511

AN:

24186

East Asian (EAS)

AF:

0.00168

AC:

AN:

39258

South Asian (SAS)

AF:

0.0768

AC:

6309

AN:

82144

European-Finnish (FIN)

AF:

0.0414

AC:

2138

AN:

51658

Middle Eastern (MID)

AF:

0.113

AC:

545

AN:

4824

European-Non Finnish (NFE)

AF:

0.0429

AC:

47153

AN:

1098800

Other (OTH)

AF:

0.0639

AC:

3768

AN:

58970

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

3188

6375

9563

12750

15938

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.100

AC:

15278

AN:

152238

Hom.:

1366

Cov.:

AF XY:

0.0980

AC XY:

7297

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.244

AC:

10125

AN:

41504

American (AMR)

AF:

0.0640

AC:

979

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0579

AC:

201

AN:

3470

East Asian (EAS)

AF:

0.00386

AC:

AN:

5180

South Asian (SAS)

AF:

0.0722

AC:

349

AN:

4832

European-Finnish (FIN)

AF:

0.0374

AC:

397

AN:

10618

Middle Eastern (MID)

AF:

0.170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0427

AC:

2902

AN:

68012

Other (OTH)

AF:

0.0952

AC:

201

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

620

1239

1859

2478

3098

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0620

Hom.:

283

Bravo

AF:

0.106

Asia WGS

AF:

0.0600

AC:

208

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

5.3

(source)

DANN

Benign

0.70

PhyloP100

-0.46

PromoterAI

0.038

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(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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chr16-67483276-C-T

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