NM_016362.5:c.214C>A

Variant names:

• chr3-10289773-G-T
• rs696217
• NM_016362.5:c.214C>A
• GHRL p.Leu72Met

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:4 O:1
• Conservation: PhyloP100: 2.30
• Publications: 196 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]

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

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

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
	BP6Reputable source reports benign		ClinVar 0-star benign — supporting (BP6); ClinVar germline classification: Benign/Likely Benign, 0 star(s).
	BA1Stand-alone benign allele frequency (>5%)		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

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	Prot: NP_057446.1 UniProt:
	GHRL NM_001302821.2		c.214C>A p.Leu72Met	missense	Exon 5 of 7	Prot: NP_001289750.1 UniProt:
	GHRL NM_001302822.2		c.214C>A p.Leu72Met	missense	Exon 4 of 6	Prot: NP_001289751.1 UniProt:

GHRL NM_016362.5

MANE Select

HGVSc / HGVSpc.214C>Ap.Leu72Met

Exon rankExon 4 of 6

missense

Prot: NP_057446.1UniProt: Q9UBU3-1

GHRL NM_001302821.2

HGVSc / HGVSpc.214C>Ap.Leu72Met

Exon rankExon 5 of 7

missense

Prot: NP_001289750.1UniProt: Q9UBU3-1

GHRL NM_001302822.2

HGVSc / HGVSpc.214C>Ap.Leu72Met

Exon rankExon 4 of 6

missense

Prot: NP_001289751.1UniProt: Q9UBU3-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	GHRL ENST00000335542.13	TSL:1MANE Select	c.214C>A p.Leu72Met	missense	Exon 4 of 6	Prot: ENSP00000335074.8 UniProt:
	GHRL ENST00000429122.1	TSL:1	c.214C>A p.Leu72Met	missense	Exon 4 of 6	Prot: ENSP00000414819.1 UniProt:
	GHRL ENST00000457360.5	TSL:1	c.214C>A p.Leu72Met	missense	Exon 4 of 6	Prot: ENSP00000391406.1 UniProt:

GHRL ENST00000335542.13

TSL:1MANE Select

HGVSc / HGVSpc.214C>Ap.Leu72Met

Exon rankExon 4 of 6

missense

Prot: ENSP00000335074.8UniProt: Q9UBU3-1

GHRL ENST00000429122.1

TSL:1

HGVSc / HGVSpc.214C>Ap.Leu72Met

Exon rankExon 4 of 6

missense

Prot: ENSP00000414819.1UniProt: Q9UBU3-1

GHRL ENST00000457360.5

TSL:1

HGVSc / HGVSpc.214C>Ap.Leu72Met

Exon rankExon 4 of 6

missense

Prot: ENSP00000391406.1UniProt: Q9UBU3-1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0728	AC:11029	Hom:565	AN:151572	Cov:31
GnomAD2 exomes	AF: 0.0877	AC:22035	Hom:	AN:251348	Cov:
GnomAD4 exome	AF: 0.0829	AC:120137	Hom:5630	AN:1450032	Cov:30
GnomAD4 genome	AF: 0.0727	AC:11026	Hom:565	AN:151692	Cov:31
TOPMed (Bravo)	AF: 0.0637	AC:16861	Hom:737	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0746	AC:30839	Hom:1271	AN:413350	Cov:
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.0726	AC:170	Hom:6	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.191	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.103	AC:31	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.0588	AC:765	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.121	AC:422	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.176	AC:1269	Hom:	AN:7230	Cov:
Qatari Genome	AF: 0.0398	AC:80	Hom:	AN:2010	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.206	AC:25124	Hom:2618	AN:121884	Cov:
Turkish Variome	AF: 0.0845	AC:564	Hom:40	AN:6676	Cov:
UK10K	AF: 0.0820	AC:620	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.202	AC:1810	Hom:196	AN:8960	Cov:

Showing 17 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.0789 *	876	11096	0.0808 *	1423	17602
BipEx(Bipolar disorder (including schizoaffective))	0.0810	2303	28420	0.0811	2338	28844
Epi25(Epilepsy)	0.0832	3490	41956	0.0774	5175	66876
SCHEMA(Schizophrenia)	0.113	14659	130044	0.112	22872	204924

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

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

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	21
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
FuncVEP CTI	Benign	0.038
GPN-Star LLR	N/A	-3.4
GPN-Star score	N/A	3.4
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
Mutation Taster	N/A	88/12	disease causing (ClinVar)
MutationAssessor	Uncertain	2.4	M
PhyloP100	Benign	2.3
popEVE	Benign	-3.2
PrimateAI	Benign	0.45	T
PromoterAI	N/A	-0.030	Neutral
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.12
Sift	Benign	0.11	T
Sift4G	Benign	0.19	T
Varity_R	N/A	0.10
VESM-3B	Benign	-5.8

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs696217;

hg19: chr3-10331457;

COSMIC: COSV55056089;

COSMIC: COSV55056089;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar