chr3-10289835-C-T

Variant names:

• chr3-10289835-C-T
• rs34911341
• NM_016362.5:c.152G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 68 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0062939525).
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016362.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHRL	NM_016362.5	MANE Select	c.152G>A	p.Arg51Gln	missense	Exon 4 of 6	NP_057446.1
	GHRL	NM_001302821.2		c.152G>A	p.Arg51Gln	missense	Exon 5 of 7	NP_001289750.1
	GHRL	NM_001302822.2		c.152G>A	p.Arg51Gln	missense	Exon 4 of 6	NP_001289751.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHRL	ENST00000335542.13	TSL:1 MANE Select	c.152G>A	p.Arg51Gln	missense	Exon 4 of 6	ENSP00000335074.8
	GHRL	ENST00000429122.1	TSL:1	c.152G>A	p.Arg51Gln	missense	Exon 4 of 6	ENSP00000414819.1
	GHRL	ENST00000457360.5	TSL:1	c.152G>A	p.Arg51Gln	missense	Exon 4 of 6	ENSP00000391406.1

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

GnomAD2 exomes AF: 0.00696 AC: 1750 AN: 251294 AF XY: 0.00700

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 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

African (AFR) AF: 0.00105 AC: 35 AN: 33476

American (AMR) AF: 0.00201 AC: 90 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00191 AC: 50 AN: 26130

East Asian (EAS) AF: 0.00113 AC: 45 AN: 39698

South Asian (SAS) AF: 0.000429 AC: 37 AN: 86252

European-Finnish (FIN) AF: 0.0246 AC: 1316 AN: 53398

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.00720 AC: 8003 AN: 1111926

Other (OTH) AF: 0.00525 AC: 317 AN: 60396

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

African (AFR) AF: 0.00135 AC: 56 AN: 41436

American (AMR) AF: 0.00203 AC: 31 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3464

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5164

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4802

European-Finnish (FIN) AF: 0.0248 AC: 263 AN: 10588

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00988 AC: 672 AN: 67982

Other (OTH) AF: 0.00525 AC: 11 AN: 2096

Alfa AF: 0.00744 Hom.: 29

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

Dec 01, 2005

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

Obesity Other:1

Dec 01, 2005

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		3.4
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.25
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.53
MVP		0.77
MPC		0.053
ClinPred		0.036	T
GERP RS		4.9
PromoterAI		0.0017	Neutral
Varity_R		0.52
gMVP		0.45
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

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