rs6180

chr5-42719137-A-Cchr5-42719137-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000163.5(GHR):c.1630A>C(p.Ile544Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 1,613,300 control chromosomes in the GnomAD database, including 162,936 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.43 ( 14368 hom., cov: 32)

Exomes 𝑓: 0.45 ( 148568 hom. )

Consequence

GHR
NM_000163.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: 1.58

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=1.2171396E-4).

BP6

Variant 5-42719137-A-C is Benign according to our data. Variant chr5-42719137-A-C is described in ClinVar as [Benign]. Clinvar id is 8658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-42719137-A-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.559 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GHR	NM_000163.5 linkuse as main transcript	c.1630A>C	p.Ile544Leu	missense_variant	10/10	ENST00000230882.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GHR	ENST00000230882.9 linkuse as main transcript	c.1630A>C	p.Ile544Leu	missense_variant	10/10	1	NM_000163.5	P1	P10912-1

Frequencies

GnomAD3 genomes

AF:

0.431

AC:

65445

AN:

151868

Hom.:

14380

Cov.:

show subpopulations

Gnomad AFR

AF:

0.391

Gnomad AMI

AF:

0.368

Gnomad AMR

AF:

0.390

Gnomad ASJ

AF:

0.445

Gnomad EAS

AF:

0.577

Gnomad SAS

AF:

0.478

Gnomad FIN

AF:

0.371

Gnomad MID

AF:

0.576

Gnomad NFE

AF:

0.459

Gnomad OTH

AF:

0.434

GnomAD3 exomes

AF:

0.436

AC:

109339

AN:

250692

Hom.:

24629

AF XY:

0.442

AC XY:

59947

AN XY:

135484

show subpopulations

Gnomad AFR exome

AF:

0.387

Gnomad AMR exome

AF:

0.325

Gnomad ASJ exome

AF:

0.432

Gnomad EAS exome

AF:

0.599

Gnomad SAS exome

AF:

0.465

Gnomad FIN exome

AF:

0.370

Gnomad NFE exome

AF:

0.455

Gnomad OTH exome

AF:

0.454

GnomAD4 exome

AF:

0.449

AC:

656062

AN:

1461314

Hom.:

148568

Cov.:

AF XY:

0.450

AC XY:

327308

AN XY:

726956

show subpopulations

Gnomad4 AFR exome

AF:

0.390

Gnomad4 AMR exome

AF:

0.335

Gnomad4 ASJ exome

AF:

0.436

Gnomad4 EAS exome

AF:

0.580

Gnomad4 SAS exome

AF:

0.463

Gnomad4 FIN exome

AF:

0.374

Gnomad4 NFE exome

AF:

0.453

Gnomad4 OTH exome

AF:

0.456

GnomAD4 genome

AF:

0.431

AC:

65438

AN:

151986

Hom.:

14368

Cov.:

AF XY:

0.431

AC XY:

31996

AN XY:

74270

show subpopulations

Gnomad4 AFR

AF:

0.390

Gnomad4 AMR

AF:

0.390

Gnomad4 ASJ

AF:

0.445

Gnomad4 EAS

AF:

0.576

Gnomad4 SAS

AF:

0.478

Gnomad4 FIN

AF:

0.371

Gnomad4 NFE

AF:

0.459

Gnomad4 OTH

AF:

0.432

Alfa

AF:

0.459

Hom.:

41173

Bravo

AF:

0.430

TwinsUK

AF:

0.446

AC:

1654

ALSPAC

AF:

0.446

AC:

1717

ESP6500AA

AF:

0.389

AC:

1714

ESP6500EA

AF:

0.461

AC:

3961

ExAC

AF:

0.443

AC:

53769

Asia WGS

AF:

0.530

AC:

1843

AN:

3478

EpiCase

AF:

0.474

EpiControl

AF:

0.466

ClinVar

Significance: Benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 17, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Laron-type isolated somatotropin defect

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
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	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 17547682, 12910492, 27862957) -

Short stature due to partial GHR deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Hypercholesterolemia, familial, 1

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Aug 30, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Uncertain

0.46

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

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Benign

0.55

MetaRNN

Benign

0.00012

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

MetaSVM

Benign

-0.91

MutationAssessor

Pathogenic

3.4

M;M;.;M;M;M;M;.

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.2

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

REVEL

Benign

0.10

Sift

Uncertain

0.0090

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

Sift4G

Benign

0.13

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

Polyphen

0.93

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

Vest4

0.14

MPC

0.28

ClinPred

0.066

GERP RS

3.4

Varity_R

0.16

gMVP

0.34

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