chr3-10289773-G-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_016362.5(GHRL):c.214C>A(p.Leu72Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0819 in 1,601,724 control chromosomes in the GnomAD database, including 6,195 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.073 ( 565 hom., cov: 31)

Exomes 𝑓: 0.083 ( 5630 hom. )

Consequence

GHRL
NM_016362.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:4O:1

Conservation

PhyloP100: 2.30

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 made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015681088).

BP6

Variant 3-10289773-G-T is Benign according to our data. Variant chr3-10289773-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 5062.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=1}.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHRL	NM_016362.5 link	c.214C>A	p.Leu72Met	missense_variant	Exon 4 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.214C>A	p.Leu72Met	missense_variant	Exon 4 of 6	1	NM_016362.5	ENSP00000335074.8		Q9UBU3-1

Frequencies

GnomAD3 genomes

AF:

0.0728

AC:

11029

AN:

151572

Hom.:

565

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0217

Gnomad AMI

AF:

0.0352

Gnomad AMR

AF:

0.0729

Gnomad ASJ

AF:

0.127

Gnomad EAS

AF:

0.195

Gnomad SAS

AF:

0.0910

Gnomad FIN

AF:

0.137

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.0811

Gnomad OTH

AF:

0.0707

GnomAD3 exomes

AF:

0.0877

AC:

22035

AN:

251348

Hom.:

1191

AF XY:

0.0898

AC XY:

12198

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.0183

Gnomad AMR exome

AF:

0.0478

Gnomad ASJ exome

AF:

0.126

Gnomad EAS exome

AF:

0.189

Gnomad SAS exome

AF:

0.0908

Gnomad FIN exome

AF:

0.131

Gnomad NFE exome

AF:

0.0807

Gnomad OTH exome

AF:

0.0888

GnomAD4 exome

AF:

0.0829

AC:

120137

AN:

1450032

Hom.:

5630

Cov.:

AF XY:

0.0834

AC XY:

60262

AN XY:

722218

show subpopulations

Gnomad4 AFR exome

AF:

0.0185

Gnomad4 AMR exome

AF:

0.0506

Gnomad4 ASJ exome

AF:

0.127

Gnomad4 EAS exome

AF:

0.193

Gnomad4 SAS exome

AF:

0.0892

Gnomad4 FIN exome

AF:

0.124

Gnomad4 NFE exome

AF:

0.0785

Gnomad4 OTH exome

AF:

0.0865

GnomAD4 genome

AF:

0.0727

AC:

11026

AN:

151692

Hom.:

565

Cov.:

AF XY:

0.0759

AC XY:

5630

AN XY:

74146

show subpopulations

Gnomad4 AFR

AF:

0.0217

Gnomad4 AMR

AF:

0.0728

Gnomad4 ASJ

AF:

0.127

Gnomad4 EAS

AF:

0.195

Gnomad4 SAS

AF:

0.0913

Gnomad4 FIN

AF:

0.137

Gnomad4 NFE

AF:

0.0810

Gnomad4 OTH

AF:

0.0705

Alfa

AF:

0.0770

Hom.:

876

Bravo

AF:

0.0637

TwinsUK

AF:

0.0833

AC:

309

ALSPAC

AF:

0.0807

AC:

311

ESP6500AA

AF:

0.0232

AC:

102

ESP6500EA

AF:

0.0771

AC:

663

ExAC

AF:

0.0856

AC:

10388

Asia WGS

AF:

0.121

AC:

422

AN:

3478

EpiCase

AF:

0.0780

EpiControl

AF:

0.0837

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inherited obesity

Uncertain:1Benign:1

Dec 19, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 17, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28481975, 25257375, 23321590, 31440212, 30487812, 24132517, 25540946, 24341728, 11502844, 12181387, 22876551, 16793966, 21195705, 18848536) -

Obesity, age at onset of

Pathogenic:1

Dec 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Obesity

Benign:1

Apr 19, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Metabolic syndrome, susceptibility to

Other:1

Dec 01, 2005

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

0.14

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

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

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.71

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

MetaRNN

Benign

0.0016

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

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

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

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.42

N;N;N;N;N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.11

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

Sift4G

Benign

0.19

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

Polyphen

1.0

D;D;.;D;D;D;D;D

Vest4

0.38

MPC

0.054

ClinPred

0.025

GERP RS

3.4

Varity_R

0.10

gMVP

0.12

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over