chr5-42719242-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000163.5(GHR):c.1735C>A(p.Pro579Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0225 in 1,613,872 control chromosomes in the GnomAD database, including 1,925 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 146 hom., cov: 33)

Exomes 𝑓: 0.023 ( 1779 hom. )

Consequence

GHR
NM_000163.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.167

Publications

34 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0011945367).

BP6

Variant 5-42719242-C-A is Benign according to our data. Variant chr5-42719242-C-A is described in ClinVar as Benign. ClinVar VariationId is 281096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHR	NM_000163.5 link	c.1735C>A	p.Pro579Thr	missense_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.1735C>A	p.Pro579Thr	missense_variant	Exon 10 of 10	1	NM_000163.5	ENSP00000230882.4		P10912-1

Frequencies

GnomAD3 genomes

AF:

0.0179

AC:

2723

AN:

152114

Hom.:

146

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00427

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0169

Gnomad ASJ

AF:

0.00893

Gnomad EAS

AF:

0.138

Gnomad SAS

AF:

0.174

Gnomad FIN

AF:

0.00368

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00910

Gnomad OTH

AF:

0.0182

GnomAD2 exomes

AF:

0.0404

AC:

10135

AN:

250926

AF XY:

0.0468

show subpopulations

Gnomad AFR exome

AF:

0.00400

Gnomad AMR exome

AF:

0.0266

Gnomad ASJ exome

AF:

0.00993

Gnomad EAS exome

AF:

0.133

Gnomad FIN exome

AF:

0.00365

Gnomad NFE exome

AF:

0.00951

Gnomad OTH exome

AF:

0.0252

GnomAD4 exome

AF:

0.0230

AC:

33558

AN:

1461642

Hom.:

1779

Cov.:

AF XY:

0.0274

AC XY:

19912

AN XY:

727140

show subpopulations

African (AFR)

AF:

0.00353

AC:

118

AN:

33474

American (AMR)

AF:

0.0259

AC:

1157

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00995

AC:

260

AN:

26130

East Asian (EAS)

AF:

0.0972

AC:

3858

AN:

39682

South Asian (SAS)

AF:

0.169

AC:

14606

AN:

86234

European-Finnish (FIN)

AF:

0.00301

AC:

161

AN:

53404

Middle Eastern (MID)

AF:

0.0420

AC:

242

AN:

5768

European-Non Finnish (NFE)

AF:

0.0102

AC:

11287

AN:

1111860

Other (OTH)

AF:

0.0310

AC:

1869

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

2081

4162

6243

8324

10405

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

624

1248

1872

2496

3120

<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:

0.0179

AC:

2726

AN:

152230

Hom.:

146

Cov.:

AF XY:

0.0205

AC XY:

1524

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.00429

AC:

178

AN:

41534

American (AMR)

AF:

0.0174

AC:

266

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00893

AC:

AN:

3470

East Asian (EAS)

AF:

0.137

AC:

707

AN:

5166

South Asian (SAS)

AF:

0.174

AC:

839

AN:

4810

European-Finnish (FIN)

AF:

0.00368

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00910

AC:

619

AN:

68024

Other (OTH)

AF:

0.0180

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

125

250

376

501

626

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.0130

Hom.:

137

Bravo

AF:

0.0160

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.00986

AC:

ESP6500AA

AF:

0.00477

AC:

ESP6500EA

AF:

0.00860

AC:

ExAC

AF:

0.0403

AC:

4892

Asia WGS

AF:

0.145

AC:

501

AN:

3478

EpiCase

AF:

0.0103

EpiControl

AF:

0.0104

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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

Significance:Benign

Review Status:no assertion criteria provided

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

- -

Jul 14, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 19344888, 19447840, 8664975, 20981092, 8421103) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

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:2

Mar 06, 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. -

Jun 29, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.77

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.37

T;T;.;T;T;T;T;.

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.091

LIST_S2

Benign

0.79

.;.;T;.;.;T;.;T

MetaRNN

Benign

0.0012

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

L;L;.;L;L;L;L;.

PhyloP100

-0.17

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.75

N;.;.;.;.;.;.;N

REVEL

Benign

0.034

Sift

Benign

0.065

T;.;.;.;.;.;.;T

Sift4G

Uncertain

0.046

D;D;D;D;D;D;D;D

Polyphen

0.0070

B;B;.;B;B;B;B;.

Vest4

0.024

MPC

0.059

ClinPred

0.0047

GERP RS

2.4

Varity_R

0.047

gMVP

0.33

Mutation Taster

=100/0

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

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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