3-172447883-G-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_198407.2(GHSR):c.531C>A(p.Pro177Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00426 in 1,613,452 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0031 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0044 ( 25 hom. )

Consequence

GHSR
NM_198407.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:6

Conservation

PhyloP100: 2.38

Variant links:

Genes affected

GHSR (HGNC:4267): (growth hormone secretagogue receptor) This gene encodes a member of the G-protein coupled receptor family. The encoded protein may play a role in energy homeostasis and regulation of body weight. Two identified transcript variants are expressed in several tissues and are evolutionary conserved in fish and swine. One transcript, 1a, excises an intron and encodes the functional protein; this protein is the receptor for the Ghrelin ligand and defines a neuroendocrine pathway for growth hormone release. The second transcript (1b) retains the intron and does not function as a receptor for Ghrelin; however, it may function to attenuate activity of isoform 1a. Mutations in this gene are associated with autosomal idiopathic short stature.[provided by RefSeq, Apr 2010]

GHSR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 3-172447883-G-T is Benign according to our data. Variant chr3-172447883-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 698005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-172447883-G-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=2.38 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHSR	NM_198407.2 link	c.531C>A	p.Pro177Pro	synonymous_variant	Exon 1 of 2	ENST00000241256.3	NP_940799.1	Q92847-1
GHSR	NM_004122.2 link	c.531C>A	p.Pro177Pro	synonymous_variant	Exon 1 of 1		NP_004113.1	Q92847-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GHSR	ENST00000241256.3 link	c.531C>A	p.Pro177Pro	synonymous_variant	Exon 1 of 2	1	NM_198407.2	ENSP00000241256.2		Q92847-1
GHSR	ENST00000427970.1 link	c.531C>A	p.Pro177Pro	synonymous_variant	Exon 1 of 1	6		ENSP00000395344.1		Q92847-2

Frequencies

GnomAD3 genomes

AF:

0.00313

AC:

477

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00386

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00535

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00343

AC:

858

AN:

250346

Hom.:

AF XY:

0.00343

AC XY:

465

AN XY:

135448

show subpopulations

Gnomad AFR exome

AF:

0.000992

Gnomad AMR exome

AF:

0.000608

Gnomad ASJ exome

AF:

0.000398

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000556

Gnomad FIN exome

AF:

0.00501

Gnomad NFE exome

AF:

0.00596

Gnomad OTH exome

AF:

0.00311

GnomAD4 exome

AF:

0.00438

AC:

6395

AN:

1461116

Hom.:

Cov.:

AF XY:

0.00425

AC XY:

3090

AN XY:

726720

show subpopulations

Gnomad4 AFR exome

AF:

0.000598

Gnomad4 AMR exome

AF:

0.000626

Gnomad4 ASJ exome

AF:

0.000574

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000649

Gnomad4 FIN exome

AF:

0.00508

Gnomad4 NFE exome

AF:

0.00519

Gnomad4 OTH exome

AF:

0.00379

GnomAD4 genome

AF:

0.00313

AC:

477

AN:

152336

Hom.:

Cov.:

AF XY:

0.00298

AC XY:

222

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.000721

Gnomad4 AMR

AF:

0.00229

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00386

Gnomad4 NFE

AF:

0.00535

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00444

Hom.:

Bravo

AF:

0.00260

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The GHSR p.Pro177Pro variant was identified in dbSNP (ID: rs4988509) but was not identified in ClinVar, Cosmic or LOVD 3.0. The p.Pro177Pro synonymous substitution was identified in a cohort of 15,854 Danes in a study aiming to identify associations between GHSR variants and obesity, however this variant was not further analyzed (Gjesing_2010_PMID: 20404923). The variant was also reported in a case-control study of height but was not analyzed (Gueorguiev_2009_PMID: 18945286). The variant was identified in control databases in 979 of 281750 chromosomes (4 homozygous) at a frequency of 0.003475 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 772 of 128364 chromosomes (freq: 0.006014), European (Finnish) in 122 of 25046 chromosomes (freq: 0.004871), Other in 22 of 7198 chromosomes (freq: 0.003056), African in 20 of 24852 chromosomes (freq: 0.000805), Latino in 22 of 35410 chromosomes (freq: 0.000621), South Asian in 17 of 30598 chromosomes (freq: 0.000556) and Ashkenazi Jewish in 4 of 10340 chromosomes (freq: 0.000387); it was not observed in the East Asian population. The p.Pro177Pro variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site, however 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GHSR: BP4, BP7, BS2 -

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Short stature due to growth hormone secretagogue receptor deficiency

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.85

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over