rs6184

Positions:

chr5-42719242-C-A

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 281096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-42719242-C-A is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
GHR	NM_000163.5 linkuse as main transcript	c.1735C>A	p.Pro579Thr	missense_variant	10/10	ENST00000230882.9	NP_000154.1	P10912-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GHR	ENST00000230882.9 linkuse as main transcript	c.1735C>A	p.Pro579Thr	missense_variant	10/10	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

GnomAD3 exomes

AF:

0.0404

AC:

10135

AN:

250926

Hom.:

731

AF XY:

0.0468

AC XY:

6351

AN XY:

135648

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 SAS exome

AF:

0.173

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

Gnomad4 AFR exome

AF:

0.00353

Gnomad4 AMR exome

AF:

0.0259

Gnomad4 ASJ exome

AF:

0.00995

Gnomad4 EAS exome

AF:

0.0972

Gnomad4 SAS exome

AF:

0.169

Gnomad4 FIN exome

AF:

0.00301

Gnomad4 NFE exome

AF:

0.0102

Gnomad4 OTH exome

AF:

0.0310

GnomAD4 genome

AF:

0.0179

AC:

2726

AN:

152230

Hom.:

146

Cov.:

AF XY:

0.0205

AC XY:

1524

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.00429

Gnomad4 AMR

AF:

0.0174

Gnomad4 ASJ

AF:

0.00893

Gnomad4 EAS

AF:

0.137

Gnomad4 SAS

AF:

0.174

Gnomad4 FIN

AF:

0.00368

Gnomad4 NFE

AF:

0.00910

Gnomad4 OTH

AF:

0.0180

Alfa

AF:

0.0125

Hom.:

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

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 14, 2016	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	This variant is associated with the following publications: (PMID: 19344888, 19447840, 8664975, 20981092, 8421103) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Laron-type isolated somatotropin defect

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 29, 2017	- -

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

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;.

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

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