rs6184

chr5-42719242-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 13/19 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.167

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]

ACMG classification

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	UniProt
GHR	NM_000163.5	c.1735C>A	p.Pro579Thr	missense_variant	10/10	ENST00000230882.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GHR	ENST00000230882.9	c.1735C>A	p.Pro579Thr	missense_variant	10/10	1	NM_000163.5	P1

Frequencies

GnomAD3 genomes AF: 0.0179 AC: 2723 AN: 152114 Hom.: 146 Cov.: 33

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

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.: 33 AF XY: 0.0274 AC XY: 19912 AN XY: 727140

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.: 33 AF XY: 0.0205 AC XY: 1524 AN XY: 74420

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.: 86

Bravo AF: 0.0160

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00986 AC: 38

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.00860 AC: 74

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:7

Revision: criteria provided, multiple submitters, no conflicts

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, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 14, 2016	- -

Laron-type isolated somatotropin defect Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 29, 2017	- -
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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
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) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.75	T
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	N
MetaRNN	Benign	0.0012	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L;.;L;L;L;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.26	T
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	T
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

Other links and lift over

dbSNP: rs6184; hg19: chr5-42719344; COSMIC: COSV50115138; COSMIC: COSV50115138;