rs4684677

Variant names:

Variant summary

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

The NM_016362.5(GHRL):c.269A>T(p.Gln90Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0696 in 1,612,592 control chromosomes in the GnomAD database, including 6,949 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.067 ( 727 hom., cov: 33)

Exomes 𝑓: 0.070 ( 6222 hom. )

Consequence

GHRL
NM_016362.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.09

Publications

79 publications found

Variant links:

Genes affected

GHRL (HGNC:18129): (ghrelin and obestatin prepropeptide) This gene encodes the ghrelin-obestatin preproprotein that is cleaved to yield two peptides, ghrelin and obestatin. Ghrelin is a powerful appetite stimulant and plays an important role in energy homeostasis. Its secretion is initiated when the stomach is empty, whereupon it binds to the growth hormone secretagogue receptor in the hypothalamus which results in the secretion of growth hormone (somatotropin). Ghrelin is thought to regulate multiple activities, including hunger, reward perception via the mesolimbic pathway, gastric acid secretion, gastrointestinal motility, and pancreatic glucose-stimulated insulin secretion. It was initially proposed that obestatin plays an opposing role to ghrelin by promoting satiety and thus decreasing food intake, but this action is still debated. Recent reports suggest multiple metabolic roles for obestatin, including regulating adipocyte function and glucose metabolism. Alternative splicing results in multiple transcript variants. In addition, antisense transcripts for this gene have been identified and may potentially regulate ghrelin-obestatin preproprotein expression. [provided by RefSeq, Nov 2014]

GHRL links:

GHRLOS (HGNC:33885): (ghrelin opposite strand/antisense RNA) This gene is an antisense gene of the ghrelin/obestatin prepropeptide gene. Alternatively spliced transcript variants have been identified and they may function as non-coding regulatory RNAs. [provided by RefSeq, Jan 2013]

GHRLOS 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=0.0018431842).

BP6

Variant 3-10286769-T-A is Benign according to our data. Variant chr3-10286769-T-A is described in ClinVar as Benign. ClinVar VariationId is 5063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHRL	NM_016362.5 link	c.269A>T	p.Gln90Leu	missense_variant	Exon 5 of 6	ENST00000335542.13	NP_057446.1	Q9UBU3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GHRL	ENST00000335542.13 link	c.269A>T	p.Gln90Leu	missense_variant	Exon 5 of 6	1	NM_016362.5	ENSP00000335074.8		Q9UBU3-1

Frequencies

GnomAD3 genomes

AF:

0.0666

AC:

10129

AN:

152170

Hom.:

718

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0151

Gnomad AMI

AF:

0.0351

Gnomad AMR

AF:

0.210

Gnomad ASJ

AF:

0.0449

Gnomad EAS

AF:

0.00673

Gnomad SAS

AF:

0.0598

Gnomad FIN

AF:

0.139

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0613

Gnomad OTH

AF:

0.0636

GnomAD2 exomes

AF:

0.104

AC:

26029

AN:

251244

AF XY:

0.0936

show subpopulations

Gnomad AFR exome

AF:

0.0119

Gnomad AMR exome

AF:

0.370

Gnomad ASJ exome

AF:

0.0401

Gnomad EAS exome

AF:

0.00566

Gnomad FIN exome

AF:

0.139

Gnomad NFE exome

AF:

0.0629

Gnomad OTH exome

AF:

0.0872

GnomAD4 exome

AF:

0.0700

AC:

102169

AN:

1460304

Hom.:

6222

Cov.:

AF XY:

0.0685

AC XY:

49801

AN XY:

726532

show subpopulations

African (AFR)

AF:

0.0108

AC:

360

AN:

33458

American (AMR)

AF:

0.354

AC:

15802

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.0408

AC:

1067

AN:

26132

East Asian (EAS)

AF:

0.0128

AC:

509

AN:

39686

South Asian (SAS)

AF:

0.0624

AC:

5377

AN:

86210

European-Finnish (FIN)

AF:

0.138

AC:

7377

AN:

53388

Middle Eastern (MID)

AF:

0.0277

AC:

160

AN:

5766

European-Non Finnish (NFE)

AF:

0.0611

AC:

67872

AN:

1110650

Other (OTH)

AF:

0.0604

AC:

3645

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

3993

7985

11978

15970

19963

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2606

5212

7818

10424

13030

<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:

0.0666

AC:

10142

AN:

152288

Hom.:

727

Cov.:

AF XY:

0.0716

AC XY:

5334

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0151

AC:

626

AN:

41566

American (AMR)

AF:

0.211

AC:

3226

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0449

AC:

156

AN:

3472

East Asian (EAS)

AF:

0.00674

AC:

AN:

5190

South Asian (SAS)

AF:

0.0592

AC:

286

AN:

4828

European-Finnish (FIN)

AF:

0.139

AC:

1478

AN:

10600

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0613

AC:

4167

AN:

68024

Other (OTH)

AF:

0.0630

AC:

133

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

462

923

1385

1846

2308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

216

324

432

540

<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:

0.0610

Hom.:

155

Bravo

AF:

0.0726

TwinsUK

AF:

0.0612

AC:

227

ALSPAC

AF:

0.0602

AC:

232

ESP6500AA

AF:

0.0143

AC:

ESP6500EA

AF:

0.0590

AC:

507

ExAC

AF:

0.0904

AC:

10981

Asia WGS

AF:

0.0470

AC:

163

AN:

3478

EpiCase

AF:

0.0573

EpiControl

AF:

0.0577

ClinVar

Significance: Benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23251435, 12050239, 25540946, 23084284) -

Obesity

Other:1

Jun 01, 2002

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

T;.;.;.;.;T;.;T

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.83

.;.;T;T;T;.;T;T

MetaRNN

Benign

0.0018

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

M;.;.;.;.;M;.;M

PhyloP100

4.1

PrimateAI

Benign

0.34

PROVEAN

Pathogenic

-4.7

D;D;D;D;D;D;D;D

REVEL

Benign

0.17

Sift

Benign

0.13

T;T;D;D;T;T;D;T

Sift4G

Benign

0.085

T;T;D;D;T;T;D;T

Polyphen

1.0

D;D;D;D;D;D;D;D

Vest4

0.40

MPC

0.053

ClinPred

0.026

GERP RS

4.8

Varity_R

0.29

gMVP

0.60

Mutation Taster

=88/12

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over