3-10289773-G-C

Variant names:

• chr3-10289773-G-C
• rs696217
• NM_016362.5:c.214C>G
• GHRL p.Leu72Val

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateB3_Supporting

The NM_016362.5(GHRL):c.214C>G (p.Leu72Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000000689 (AC=1) in the gnomAD database across 1,451,160 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000000907. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.L72M: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 5062)

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GHRL NM_016362.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.30
• Publications: 104 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 ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = 0.000001, AC = 1 — absent/extremely rare (O3 moderate [+2])
	B3Computational evidence does not support deleterious effect		Computational evidence does not support a deleterious effect; Missense variant — primary computational scorer does not support an oncogenic/deleterious effect; supports B3

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>G p.Leu72Val	missense	Exon 4 of 6	Prot: NP_057446.1 UniProt:
	GHRL NM_001302821.2		c.214C>G p.Leu72Val	missense	Exon 5 of 7	Prot: NP_001289750.1 UniProt:
	GHRL NM_001302822.2		c.214C>G p.Leu72Val	missense	Exon 4 of 6	Prot: NP_001289751.1 UniProt:

GHRL NM_016362.5

MANE Select

HGVSc / HGVSpc.214C>Gp.Leu72Val

Exon rankExon 4 of 6

missense

Prot: NP_057446.1UniProt: Q9UBU3-1

GHRL NM_001302821.2

HGVSc / HGVSpc.214C>Gp.Leu72Val

Exon rankExon 5 of 7

missense

Prot: NP_001289750.1UniProt: Q9UBU3-1

GHRL NM_001302822.2

HGVSc / HGVSpc.214C>Gp.Leu72Val

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>G p.Leu72Val	missense	Exon 4 of 6	Prot: ENSP00000335074.8 UniProt:
	GHRL ENST00000429122.1	TSL:1	c.214C>G p.Leu72Val	missense	Exon 4 of 6	Prot: ENSP00000414819.1 UniProt:
	GHRL ENST00000457360.5	TSL:1	c.214C>G p.Leu72Val	missense	Exon 4 of 6	Prot: ENSP00000391406.1 UniProt:

GHRL ENST00000335542.13

TSL:1MANE Select

HGVSc / HGVSpc.214C>Gp.Leu72Val

Exon rankExon 4 of 6

missense

Prot: ENSP00000335074.8UniProt: Q9UBU3-1

GHRL ENST00000429122.1

TSL:1

HGVSc / HGVSpc.214C>Gp.Leu72Val

Exon rankExon 4 of 6

missense

Prot: ENSP00000414819.1UniProt: Q9UBU3-1

GHRL ENST00000457360.5

TSL:1

HGVSc / HGVSpc.214C>Gp.Leu72Val

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 exome	AF: 6.89e-7	AC:1	Hom:0	AN:1451160	Cov:30
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:31
Local & regional cohorts 1 source Population-specific and national genomic databases
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000112	AC:1	Hom:0	AN:8960	Cov:

Showing 4 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	21
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.79	D
FuncVEP CTI	Benign	0.20
GPN-Star LLR	N/A	-3.4
GPN-Star score	N/A	3.4
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.82	T
Mutation Taster	N/A	92/8	polymorphism
MutationAssessor	Benign	1.8	L
PhyloP100	Benign	2.3
popEVE	Benign	-3.0
PrimateAI	Benign	0.43	T
PromoterAI	N/A	-0.010	Neutral
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.061
Sift	Benign	0.16	T
Sift4G	Benign	0.36	T
Varity_R	N/A	0.095
VESM-3B	Benign	-5.2

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.010	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;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar