rs6176

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000163.5(GHR):c.1473C>T(p.Ser491Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0236 in 1,611,654 control chromosomes in the GnomAD database, including 564 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 42 hom., cov: 32)

Exomes 𝑓: 0.024 ( 522 hom. )

Consequence

GHR
NM_000163.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.214

Publications

7 publications found

Variant links:

Genes affected

GHR (HGNC:4263): (growth hormone receptor) This gene encodes a member of the type I cytokine receptor family, which is a transmembrane receptor for growth hormone. Binding of growth hormone to the receptor leads to receptor dimerization and the activation of an intra- and intercellular signal transduction pathway leading to growth. Mutations in this gene have been associated with Laron syndrome, also known as the growth hormone insensitivity syndrome (GHIS), a disorder characterized by short stature. In humans and rabbits, but not rodents, growth hormone binding protein (GHBP) is generated by proteolytic cleavage of the extracellular ligand-binding domain from the mature growth hormone receptor protein. Multiple alternatively spliced transcript variants have been found for this gene.[provided by RefSeq, Jun 2011]

GHR Gene-Disease associations (from GenCC):

Laron syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
short stature due to partial GHR deficiency
Inheritance: Unknown, AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

GHR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 5-42718980-C-T is Benign according to our data. Variant chr5-42718980-C-T is described in ClinVar as [Benign]. Clinvar id is 255404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.214 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0583 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHR	NM_000163.5 link	c.1473C>T	p.Ser491Ser	synonymous_variant	Exon 10 of 10	ENST00000230882.9	NP_000154.1	P10912-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GHR	ENST00000230882.9 link	c.1473C>T	p.Ser491Ser	synonymous_variant	Exon 10 of 10	1	NM_000163.5	ENSP00000230882.4		P10912-1

Frequencies

GnomAD3 genomes

AF:

0.0208

AC:

3161

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00795

Gnomad AMI

AF:

0.0406

Gnomad AMR

AF:

0.0268

Gnomad ASJ

AF:

0.0398

Gnomad EAS

AF:

0.0193

Gnomad SAS

AF:

0.0238

Gnomad FIN

AF:

0.0141

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0266

Gnomad OTH

AF:

0.0273

GnomAD2 exomes

AF:

0.0226

AC:

5657

AN:

250096

AF XY:

0.0240

show subpopulations

Gnomad AFR exome

AF:

0.00695

Gnomad AMR exome

AF:

0.0162

Gnomad ASJ exome

AF:

0.0451

Gnomad EAS exome

AF:

0.0182

Gnomad FIN exome

AF:

0.0147

Gnomad NFE exome

AF:

0.0250

Gnomad OTH exome

AF:

0.0280

GnomAD4 exome

AF:

0.0239

AC:

34875

AN:

1459480

Hom.:

522

Cov.:

AF XY:

0.0243

AC XY:

17651

AN XY:

725700

show subpopulations

African (AFR)

AF:

0.00886

AC:

296

AN:

33416

American (AMR)

AF:

0.0178

AC:

794

AN:

44634

Ashkenazi Jewish (ASJ)

AF:

0.0468

AC:

1216

AN:

26006

East Asian (EAS)

AF:

0.0240

AC:

952

AN:

39662

South Asian (SAS)

AF:

0.0289

AC:

2483

AN:

85998

European-Finnish (FIN)

AF:

0.0148

AC:

787

AN:

53332

Middle Eastern (MID)

AF:

0.0637

AC:

367

AN:

5764

European-Non Finnish (NFE)

AF:

0.0238

AC:

26444

AN:

1110376

Other (OTH)

AF:

0.0255

AC:

1536

AN:

60292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

1966

3932

5897

7863

9829

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0208

AC:

3160

AN:

152174

Hom.:

Cov.:

AF XY:

0.0204

AC XY:

1517

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.00793

AC:

329

AN:

41510

American (AMR)

AF:

0.0267

AC:

408

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0398

AC:

138

AN:

3470

East Asian (EAS)

AF:

0.0193

AC:

100

AN:

5172

South Asian (SAS)

AF:

0.0239

AC:

115

AN:

4818

European-Finnish (FIN)

AF:

0.0141

AC:

149

AN:

10602

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0266

AC:

1809

AN:

67998

Other (OTH)

AF:

0.0270

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

166

332

497

663

829

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0250

Hom.:

Bravo

AF:

0.0208

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0263

EpiControl

AF:

0.0312

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Sep 01, 2020

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Feb 03, 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:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Laron-type isolated somatotropin defect

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

8.2

(source)

DANN

Benign

0.85

PhyloP100

-0.21

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs6176

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over