rs121909362

Positions:

chr5-42699919-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM1BP4_ModerateBS1BS2

The NM_000163.5(GHR):c.535C>T(p.Arg179Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00458 in 1,595,748 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R179H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0040 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0046 ( 19 hom. )

Consequence

GHR
NM_000163.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4B:5

Conservation

PhyloP100: 1.30

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 -8 ACMG points.

PM1

In a topological_domain Extracellular (size 245) in uniprot entity GHR_HUMAN there are 39 pathogenic changes around while only 4 benign (91%) in NM_000163.5

BP4

Computational evidence support a benign effect (MetaRNN=0.085534275).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00402 (612/152228) while in subpopulation AMR AF= 0.00759 (116/15290). AF 95% confidence interval is 0.00647. There are 3 homozygotes in gnomad4. There are 307 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GHR	NM_000163.5 linkuse as main transcript	c.535C>T	p.Arg179Cys	missense_variant	6/10	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.535C>T	p.Arg179Cys	missense_variant	6/10	1	NM_000163.5	ENSP00000230882.4		P10912-1

Frequencies

GnomAD3 genomes

AF:

0.00402

AC:

612

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000966

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00760

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00227

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00597

Gnomad OTH

AF:

0.00336

GnomAD3 exomes

AF:

0.00391

AC:

980

AN:

250850

Hom.:

AF XY:

0.00396

AC XY:

537

AN XY:

135536

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.00273

Gnomad ASJ exome

AF:

0.00239

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00310

Gnomad FIN exome

AF:

0.00287

Gnomad NFE exome

AF:

0.00584

Gnomad OTH exome

AF:

0.00458

GnomAD4 exome

AF:

0.00464

AC:

6702

AN:

1443520

Hom.:

Cov.:

AF XY:

0.00462

AC XY:

3323

AN XY:

719324

show subpopulations

Gnomad4 AFR exome

AF:

0.00111

Gnomad4 AMR exome

AF:

0.00305

Gnomad4 ASJ exome

AF:

0.00177

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00301

Gnomad4 FIN exome

AF:

0.00337

Gnomad4 NFE exome

AF:

0.00529

Gnomad4 OTH exome

AF:

0.00402

GnomAD4 genome

AF:

0.00402

AC:

612

AN:

152228

Hom.:

Cov.:

AF XY:

0.00413

AC XY:

307

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.000963

Gnomad4 AMR

AF:

0.00759

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00270

Gnomad4 FIN

AF:

0.00227

Gnomad4 NFE

AF:

0.00597

Gnomad4 OTH

AF:

0.00332

Alfa

AF:

0.00555

Hom.:

Bravo

AF:

0.00385

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00814

AC:

ExAC

AF:

0.00409

AC:

496

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:4Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 13, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	GHR: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2021	This variant is associated with the following publications: (PMID: 7565946, 17462934, 8504296, 28498917, 29748515, 29073591, 27914676, 32935225) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Short stature due to partial GHR deficiency

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 26, 1995

- -

Laron-type isolated somatotropin defect;C0745103:Hypercholesterolemia, familial, 1;C1858656:Short stature due to partial GHR deficiency;C5887324:Short stature due to growth hormone secretagogue receptor deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

GHR-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 16, 2023

The GHR c.535C>T variant is predicted to result in the amino acid substitution p.Arg179Cys. This variant was reported in homozygous state in an individual with Laron dwarfism (Amselem et al. 1993. PubMed ID: 8504296) and in heterozygous state in several individuals with idiopathic short stature (Goddard et al. 1995. PubMed ID: 7565946; Sjoberg et al. 2001. PubMed ID: 11549678; Meyer et al. 2007. PubMed ID: 17462934; Barrio-Ollero et al. 2016. PubMed ID: 27914676; Mohammadian Khonsari et al. 2020. PubMed ID: 32935225). This variant is reported in 0.59% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-42700021-C-T). This frequency is higher than would be expected for causative variants in this gene. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Laron-type isolated somatotropin defect;C1858656:Short stature due to partial GHR deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

May 09, 2016

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 01, 2023

Variant summary: GHR c.535C>T (p.Arg179Cys) results in a non-conservative amino acid change located in the fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0039 in 282250 control chromosomes in the gnomAD database, including 5 homozygotes. The observed variant frequency is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in GHR causing Growth Hormone Insensitivity phenotype (0.0035). These data suggest that the variant is benign. c.535C>T has been reported in the literature as a biallelic genotype in individuals affected with or suspected of Growth Hormone Insensitivity (e.g. Amselem_1993, Goddard_1995, Woods_1997). However, these reports do not provide unequivocal conclusions about association of the variant with Growth Hormone Insensitivity. At least one publication reports experimental evidence evaluating an impact on protein function and found that the variant had a dissociation constant approximately 2-fold higher than that reported for the WT protein, however the impact on GHR activity in vitro was not examined (Goddard_1995). The following publications have been ascertained in the context of this evaluation (PMID: 8504296, 7565946, 11502828, 9360502). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Four submitters classified the variant as uncertain significance and three classified it as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Laron-type isolated somatotropin defect

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.078

BayesDel_noAF

Uncertain

0.12

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

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

Eigen

Benign

-0.034

Eigen_PC

Benign

0.012

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.79

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

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.086

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

MetaSVM

Uncertain

0.17

MutationAssessor

Benign

1.0

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

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.79

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

REVEL

Uncertain

0.61

Sift

Pathogenic

0.0

D;.;.;.;.;.;.;D;.

Sift4G

Pathogenic

0.0

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

Polyphen

0.72

P;P;.;P;P;P;P;.;.

Vest4

0.65

MVP

0.98

MPC

0.061

ClinPred

0.047

GERP RS

3.2

Varity_R

0.71

gMVP

0.68

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