rs2075356

Variant names:

• chr3-10287125-T-C
• rs2075356
• NM_016362.5:c.226-313A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016362.5(GHRL):​c.226-313A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0919 in 199,714 control chromosomes in the GnomAD database, including 1,161 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.087 (808 hom., cov: 33)
  • Exomes 𝑓: 0.11 (353 hom.)
• Consequence: GHRL NM_016362.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.195
• Publications: 30 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 3-10287125-T-C is Benign according to our data. Variant chr3-10287125-T-C is described in ClinVar as Benign. ClinVar VariationId is 1263639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.259 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHRL	NM_016362.5	MANE Select	c.226-313A>G		intron	N/A	NP_057446.1	Q9UBU3-1
	GHRL	NM_001302821.2		c.226-313A>G		intron	N/A	NP_001289750.1	Q9UBU3-1
	GHRL	NM_001302822.2		c.226-313A>G		intron	N/A	NP_001289751.1	Q9UBU3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHRL	ENST00000335542.13	TSL:1 MANE Select	c.226-313A>G		intron	N/A	ENSP00000335074.8	Q9UBU3-1
	GHRL	ENST00000429122.1	TSL:1	c.226-313A>G		intron	N/A	ENSP00000414819.1	Q9UBU3-1
	GHRL	ENST00000457360.5	TSL:1	c.226-313A>G		intron	N/A	ENSP00000391406.1	Q9UBU3-1

Frequencies

GnomAD3 genomes AF: 0.0868 AC: 13210 AN: 152156 Hom.: 807 Cov.: 33

Gnomad AFR AF: 0.0257

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.0793

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.271

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.0976

Gnomad OTH AF: 0.0879

GnomAD4 exome AF: 0.108 AC: 5143 AN: 47440 Hom.: 353 Cov.: 0 AF XY: 0.111 AC XY: 2780 AN XY: 25150

African (AFR) AF: 0.0232 AC: 36 AN: 1552

American (AMR) AF: 0.0830 AC: 161 AN: 1940

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 205 AN: 1326

East Asian (EAS) AF: 0.272 AC: 582 AN: 2136

South Asian (SAS) AF: 0.118 AC: 635 AN: 5396

European-Finnish (FIN) AF: 0.128 AC: 472 AN: 3688

Middle Eastern (MID) AF: 0.138 AC: 26 AN: 188

European-Non Finnish (NFE) AF: 0.0960 AC: 2732 AN: 28454

Other (OTH) AF: 0.107 AC: 294 AN: 2760

GnomAD4 genome AF: 0.0867 AC: 13204 AN: 152274 Hom.: 808 Cov.: 33 AF XY: 0.0899 AC XY: 6694 AN XY: 74442

African (AFR) AF: 0.0257 AC: 1067 AN: 41552

American (AMR) AF: 0.0791 AC: 1210 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 540 AN: 3468

East Asian (EAS) AF: 0.271 AC: 1401 AN: 5176

South Asian (SAS) AF: 0.118 AC: 568 AN: 4828

European-Finnish (FIN) AF: 0.144 AC: 1523 AN: 10608

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.0975 AC: 6634 AN: 68026

Other (OTH) AF: 0.0884 AC: 187 AN: 2116

Alfa AF: 0.0818 Hom.: 67

Bravo AF: 0.0771

Asia WGS AF: 0.174 AC: 605 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.5
DANN	Benign	0.82
PhyloP100		-0.20
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs2075356; hg19: chr3-10328809; COSMIC: COSV55055123; COSMIC: COSV55055123;