5-42699942-A-G

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.558A>G(p.Gly186Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.713 in 1,596,728 control chromosomes in the GnomAD database, including 410,555 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.65 ( 33294 hom., cov: 32)

Exomes 𝑓: 0.72 ( 377261 hom. )

Consequence

GHR
NM_000163.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.163

Publications

33 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=-0.51).

BP6

Variant 5-42699942-A-G is Benign according to our data. Variant chr5-42699942-A-G is described in ClinVar as Benign. ClinVar VariationId is 198051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.163 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.821 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHR	NM_000163.5 link	c.558A>G	p.Gly186Gly	synonymous_variant	Exon 6 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.558A>G	p.Gly186Gly	synonymous_variant	Exon 6 of 10	1	NM_000163.5	ENSP00000230882.4		P10912-1

Frequencies

GnomAD3 genomes

AF:

0.648

AC:

98504

AN:

151936

Hom.:

33283

Cov.:

show subpopulations

Gnomad AFR

AF:

0.443

Gnomad AMI

AF:

0.597

Gnomad AMR

AF:

0.738

Gnomad ASJ

AF:

0.702

Gnomad EAS

AF:

0.841

Gnomad SAS

AF:

0.685

Gnomad FIN

AF:

0.697

Gnomad MID

AF:

0.684

Gnomad NFE

AF:

0.726

Gnomad OTH

AF:

0.644

GnomAD2 exomes

AF:

0.717

AC:

179881

AN:

250752

AF XY:

0.715

show subpopulations

Gnomad AFR exome

AF:

0.435

Gnomad AMR exome

AF:

0.809

Gnomad ASJ exome

AF:

0.694

Gnomad EAS exome

AF:

0.848

Gnomad FIN exome

AF:

0.694

Gnomad NFE exome

AF:

0.727

Gnomad OTH exome

AF:

0.707

GnomAD4 exome

AF:

0.720

AC:

1039709

AN:

1444674

Hom.:

377261

Cov.:

AF XY:

0.719

AC XY:

517201

AN XY:

719804

show subpopulations

African (AFR)

AF:

0.431

AC:

14308

AN:

33202

American (AMR)

AF:

0.799

AC:

35629

AN:

44588

Ashkenazi Jewish (ASJ)

AF:

0.697

AC:

18134

AN:

26018

East Asian (EAS)

AF:

0.878

AC:

34776

AN:

39590

South Asian (SAS)

AF:

0.678

AC:

58233

AN:

85926

European-Finnish (FIN)

AF:

0.697

AC:

37232

AN:

53396

Middle Eastern (MID)

AF:

0.649

AC:

3729

AN:

5742

European-Non Finnish (NFE)

AF:

0.726

AC:

795840

AN:

1096384

Other (OTH)

AF:

0.699

AC:

41828

AN:

59828

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

13450

26900

40350

53800

67250

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19562

39124

58686

78248

97810

<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:

0.648

AC:

98533

AN:

152054

Hom.:

33294

Cov.:

AF XY:

0.652

AC XY:

48468

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.442

AC:

18337

AN:

41454

American (AMR)

AF:

0.738

AC:

11277

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.702

AC:

2434

AN:

3468

East Asian (EAS)

AF:

0.842

AC:

4356

AN:

5174

South Asian (SAS)

AF:

0.686

AC:

3309

AN:

4822

European-Finnish (FIN)

AF:

0.697

AC:

7360

AN:

10560

Middle Eastern (MID)

AF:

0.680

AC:

200

AN:

294

European-Non Finnish (NFE)

AF:

0.726

AC:

49354

AN:

67982

Other (OTH)

AF:

0.647

AC:

1363

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1652

3304

4957

6609

8261

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

790

1580

2370

3160

3950

<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:

0.696

Hom.:

30420

Bravo

AF:

0.642

Asia WGS

AF:

0.758

AC:

2637

AN:

3478

EpiCase

AF:

0.726

EpiControl

AF:

0.719

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Jun 30, 2014

Eurofins Ntd Llc (ga)

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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laron-type isolated somatotropin defect

Benign:3

Jun 29, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 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. -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 21, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Short stature due to partial GHR deficiency

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

6.2

(source)

DANN

Benign

0.71

PhyloP100

0.16

Mutation Taster

=294/6

polymorphism (auto)

(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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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