NM_016362.5:c.214C>A

Variant names:

Variant summary

Our verdict is The variant received -11 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_ModerateBP6

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 cumulative frequency of 0.0819 (AC=131,163) in the gnomAD database across 1,601,724 control chromosomes, including 6,195 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.19. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

Frequency

Genomes: 𝑓 0.073 ( 565 hom., cov: 31)

Exomes 𝑓: 0.083 ( 5630 hom. )

Consequence

GHRL
NM_016362.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:4O:1

Conservation

PhyloP100: 2.30

Publications

190 publications found

Variant links:

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]

GHRL links:

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]

GHRLOS links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_016362.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -11 points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

BP6

ClinVar 0-star benign — supporting (BP6); ClinVar germline classification: Benign/Likely Benign, 0 star(s).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.1896 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

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

RefSeq Transcripts

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

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.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0834

AC XY:

60262

AN XY:

722218

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

4784

9567

14351

19134

23918

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3274

6548

9822

13096

16370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0727

AC:

11026

AN:

151692

Hom.:

565

Cov.:

AF XY:

0.0759

AC XY:

5630

AN XY:

74146

show subpopulations

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.0810

AC:

5500

AN:

67882

Other (OTH)

AF:

0.0705

AC:

148

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

481

962

1443

1924

2405

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

264

396

528

660

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0761

Hom.:

1197

Bravo

AF:

0.0637

Asia WGS

AF:

0.121

AC:

422

AN:

3478

EpiCase

AF:

0.0780

EpiControl

AF:

0.0837

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.206

AC:

25124

AN:

121884

Turkish Variome

AF:

0.0845

AC:

564

AN:

6676

Hom.:

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.202

AC:

1810

AN:

8960

Hom.:

196

ABraOM SABE-WGS-1171

AF:

0.0726

AC:

170

AN:

2342

Hom.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inherited obesity (2)

not provided (2)

Obesity (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

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.71

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

PhyloP100

2.3

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.42

REVEL

Benign

0.12

Sift

Benign

0.11

Sift4G

Benign

0.19

PromoterAI

-0.030

Neutral

(source)

Varity_R

0.10

gMVP

0.12

Mutation Taster

=88/12

disease causing (ClinVar)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over