rs4684677

Positions:

chr3-10286769-T-A

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id 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/exons	MANE	Protein	UniProt
GHRL	NM_016362.5 linkuse as main transcript	c.269A>T	p.Gln90Leu	missense_variant	5/6	ENST00000335542.13	NP_057446.1
GHRLOS	NR_024145.2 linkuse as main transcript	n.397+916T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GHRL	ENST00000335542.13 linkuse as main transcript	c.269A>T	p.Gln90Leu	missense_variant	5/6	1	NM_016362.5	ENSP00000335074	P4	Q9UBU3-1
GHRLOS	ENST00000439539.3 linkuse as main transcript	n.101-645T>A		intron_variant, non_coding_transcript_variant		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

GnomAD3 exomes

AF:

0.104

AC:

26029

AN:

251244

Hom.:

3204

AF XY:

0.0936

AC XY:

12715

AN XY:

135792

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 SAS exome

AF:

0.0616

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

Gnomad4 AFR exome

AF:

0.0108

Gnomad4 AMR exome

AF:

0.354

Gnomad4 ASJ exome

AF:

0.0408

Gnomad4 EAS exome

AF:

0.0128

Gnomad4 SAS exome

AF:

0.0624

Gnomad4 FIN exome

AF:

0.138

Gnomad4 NFE exome

AF:

0.0611

Gnomad4 OTH exome

AF:

0.0604

GnomAD4 genome

AF:

0.0666

AC:

10142

AN:

152288

Hom.:

727

Cov.:

AF XY:

0.0716

AC XY:

5334

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0151

Gnomad4 AMR

AF:

0.211

Gnomad4 ASJ

AF:

0.0449

Gnomad4 EAS

AF:

0.00674

Gnomad4 SAS

AF:

0.0592

Gnomad4 FIN

AF:

0.139

Gnomad4 NFE

AF:

0.0613

Gnomad4 OTH

AF:

0.0630

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	This variant is associated with the following publications: (PMID: 23251435, 12050239, 25540946, 23084284) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Obesity

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jun 01, 2002

- -

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

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

MutationTaster

Benign

0.20

P;P;P;P;P;P;P;P;P;P;P;P

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

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

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