rs696217

Variant names:

• chr3-10289773-G-T
• rs696217
• NM_016362.5:c.214C>A

Your query was ambiguous. Multiple possible variants found:

• chr3-10289773-G-T
• chr3-10289773-G-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.073 (565 hom., cov: 31)
  • Exomes 𝑓: 0.083 (5630 hom.)
• Consequence: GHRL NM_016362.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:4 O:1
• Conservation: PhyloP100: 2.30
• Publications: 190 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 -13 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 Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 5062.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.185 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.214C>A	p.Leu72Met	missense	Exon 4 of 6	NP_057446.1	Q9UBU3-1
	GHRL	NM_001302821.2		c.214C>A	p.Leu72Met	missense	Exon 5 of 7	NP_001289750.1	Q9UBU3-1
	GHRL	NM_001302822.2		c.214C>A	p.Leu72Met	missense	Exon 4 of 6	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.214C>A	p.Leu72Met	missense	Exon 4 of 6	ENSP00000335074.8	Q9UBU3-1
	GHRL	ENST00000429122.1	TSL:1	c.214C>A	p.Leu72Met	missense	Exon 4 of 6	ENSP00000414819.1	Q9UBU3-1
	GHRL	ENST00000457360.5	TSL:1	c.214C>A	p.Leu72Met	missense	Exon 4 of 6	ENSP00000391406.1	Q9UBU3-1

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

GnomAD2 exomes AF: 0.0877 AC: 22035 AN: 251348 AF XY: 0.0898

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 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

African (AFR) AF: 0.0185 AC: 617 AN: 33296

American (AMR) AF: 0.0506 AC: 2263 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 3319 AN: 26058

East Asian (EAS) AF: 0.193 AC: 7658 AN: 39630

South Asian (SAS) AF: 0.0892 AC: 7673 AN: 86014

European-Finnish (FIN) AF: 0.124 AC: 6606 AN: 53370

Middle Eastern (MID) AF: 0.0611 AC: 351 AN: 5740

European-Non Finnish (NFE) AF: 0.0785 AC: 86466 AN: 1101286

Other (OTH) AF: 0.0865 AC: 5184 AN: 59928

GnomAD4 genome AF: 0.0727 AC: 11026 AN: 151692 Hom.: 565 Cov.: 31 AF XY: 0.0759 AC XY: 5630 AN XY: 74146

African (AFR) AF: 0.0217 AC: 898 AN: 41366

American (AMR) AF: 0.0728 AC: 1109 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 440 AN: 3466

East Asian (EAS) AF: 0.195 AC: 1001 AN: 5132

South Asian (SAS) AF: 0.0913 AC: 438 AN: 4796

European-Finnish (FIN) AF: 0.137 AC: 1436 AN: 10512

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0810 AC: 5500 AN: 67882

Other (OTH) AF: 0.0705 AC: 148 AN: 2100

Alfa AF: 0.0761 Hom.: 1197

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Inherited obesity (2)
-	-	2	not provided (2)
-	-	1	Obesity (1)
1	-	-	Obesity, age at onset of (1)
-	-	-	Metabolic syndrome, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.3
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.12
Sift	Benign	0.11	T
Sift4G	Benign	0.19	T
Polyphen		1.0	D
Vest4		0.38
MPC		0.054
ClinPred		0.025	T
GERP RS		3.4
PromoterAI		-0.030	Neutral
Varity_R		0.10
gMVP		0.12
Mutation Taster		=88/12	disease causing (ClinVar)

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