3-10289835-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_016362.5(GHRL):c.152G>A(p.Arg51Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00681 in 1,613,766 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).

• Frequency:
  • Genomes: 𝑓 0.0071 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0068 (65 hom.)
• Consequence: GHRL NM_016362.5 missense
• Clinical Significance: risk factor no assertion criteria provided O:2
• Conservation: PhyloP100: 3.38

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0062939525).
• BS2: High Homozygotes in GnomAd at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GHRL	NM_016362.5	c.152G>A	p.Arg51Gln	missense_variant	4/6	ENST00000335542.13
GHRLOS	NR_024145.2	n.555+1733C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GHRL	ENST00000335542.13	c.152G>A	p.Arg51Gln	missense_variant	4/6	1	NM_016362.5	P4
GHRLOS	ENST00000439539.3	n.326+1733C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00712 AC: 1081 AN: 151884 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00131

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0248

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00988

Gnomad OTH AF: 0.00530

GnomAD3 exomes AF: 0.00696 AC: 1750 AN: 251294 Hom.: 13 AF XY: 0.00700 AC XY: 950 AN XY: 135810

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.00141

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.0244

Gnomad NFE exome AF: 0.00911

Gnomad OTH exome AF: 0.00734

GnomAD4 exome AF: 0.00677 AC: 9902 AN: 1461764 Hom.: 65 Cov.: 31 AF XY: 0.00677 AC XY: 4920 AN XY: 727186

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00201

Gnomad4 ASJ exome AF: 0.00191

Gnomad4 EAS exome AF: 0.00113

Gnomad4 SAS exome AF: 0.000429

Gnomad4 FIN exome AF: 0.0246

Gnomad4 NFE exome AF: 0.00720

Gnomad4 OTH exome AF: 0.00525

GnomAD4 genome AF: 0.00712 AC: 1082 AN: 152002 Hom.: 12 Cov.: 32 AF XY: 0.00733 AC XY: 545 AN XY: 74310

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00155

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0248

Gnomad4 NFE AF: 0.00988

Gnomad4 OTH AF: 0.00525

Alfa AF: 0.00728 Hom.: 10

Bravo AF: 0.00456

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00616 AC: 53

ExAC AF: 0.00690 AC: 838

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00573

EpiControl AF: 0.00664

ClinVar

Significance: risk factor

Submissions summary: Other:2

Revision: no assertion criteria provided

Submissions by phenotype

Metabolic syndrome, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Dec 01, 2005

- -

Obesity 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	0.17
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.59	D;.;.;.;.;.;D;D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.84	D
MetaRNN	Benign	0.0063	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.9	M;.;M;.;.;.;M;M
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.6	D;D;D;D;D;D;D;D
REVEL	Benign	0.25
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;T;D;D;D;D
Polyphen		1.0	D;D;.;D;D;D;D;D
Vest4		0.53
MVP		0.77
MPC		0.053
ClinPred		0.036	T
GERP RS		4.9
Varity_R		0.52
gMVP		0.45

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: rs34911341; hg19: chr3-10331519; COSMIC: COSV55056594; COSMIC: COSV55056594;