3-10289773-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.073 (565 hom., cov: 31)
  • Exomes 𝑓: 0.083 (5630 hom.)
• Consequence: GHRL NM_016362.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:2 O:1
• Conservation: PhyloP100: 2.30

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]

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]

ACMG classification

Verdict is Benign. Variant got -20 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 [Likely_benign]. Clinvar id is 5062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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/exons	MANE	UniProt
GHRL	NM_016362.5	c.214C>A	p.Leu72Met	missense_variant	4/6	ENST00000335542.13
GHRLOS	NR_024145.2	n.555+1671G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GHRL	ENST00000335542.13	c.214C>A	p.Leu72Met	missense_variant	4/6	1	NM_016362.5	P4
GHRLOS	ENST00000439539.3	n.326+1671G>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0728 AC: 11029 AN: 151572 Hom.: 565 Cov.: 31

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

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.: 30 AF XY: 0.0834 AC XY: 60262 AN XY: 722218

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.: 31 AF XY: 0.0759 AC XY: 5630 AN XY: 74146

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: Benign/Likely benign

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

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Obesity, age at onset of Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2005

- -

Obesity Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 19, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

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

Metabolic syndrome, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Dec 01, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	23
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	D
MetaRNN	Benign	0.0016	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;.;M;.;.;.;M;M
MutationTaster	Benign	0.98	P;P;P;P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.45	T
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	T
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

Other links and lift over

dbSNP: rs696217; hg19: chr3-10331457; COSMIC: COSV55056089; COSMIC: COSV55056089;