5-42718826-G-T

Variant names:

• chr5-42718826-G-T
• rs6182
• NM_000163.5:c.1319G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000163.5(GHR):​c.1319G>T​(p.Cys440Phe) 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 1,614,006 control chromosomes in the GnomAD database, including 1,923 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 (144 hom., cov: 32)
  • Exomes 𝑓: 0.023 (1779 hom.)
• Consequence: GHR NM_000163.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0140
• Publications: 25 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012555122).
• BP6: Variant 5-42718826-G-T is Benign according to our data. Variant chr5-42718826-G-T is described in ClinVar as Benign. ClinVar VariationId is 281095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000163.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHR	NM_000163.5	MANE Select	c.1319G>T	p.Cys440Phe	missense	Exon 10 of 10	NP_000154.1
	GHR	NM_001242399.2		c.1340G>T	p.Cys447Phe	missense	Exon 10 of 10	NP_001229328.1
	GHR	NM_001242400.2		c.1319G>T	p.Cys440Phe	missense	Exon 11 of 11	NP_001229329.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHR	ENST00000230882.9	TSL:1 MANE Select	c.1319G>T	p.Cys440Phe	missense	Exon 10 of 10	ENSP00000230882.4
	GHR	ENST00000620156.4	TSL:5	c.1340G>T	p.Cys447Phe	missense	Exon 10 of 10	ENSP00000483403.1
	GHR	ENST00000537449.5	TSL:5	c.1319G>T	p.Cys440Phe	missense	Exon 10 of 10	ENSP00000442206.2

Frequencies

GnomAD3 genomes AF: 0.0179 AC: 2724 AN: 152050 Hom.: 145 Cov.: 32

Gnomad AFR AF: 0.00425

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: 0.00915

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.0404 AC: 10140 AN: 251082 AF XY: 0.0468

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: 0.00953

Gnomad OTH exome AF: 0.0251

GnomAD4 exome AF: 0.0230 AC: 33568 AN: 1461840 Hom.: 1779 Cov.: 34 AF XY: 0.0274 AC XY: 19923 AN XY: 727232

African (AFR) AF: 0.00352 AC: 118 AN: 33480

American (AMR) AF: 0.0259 AC: 1157 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00995 AC: 260 AN: 26136

East Asian (EAS) AF: 0.0972 AC: 3859 AN: 39696

South Asian (SAS) AF: 0.169 AC: 14612 AN: 86256

European-Finnish (FIN) AF: 0.00302 AC: 161 AN: 53394

Middle Eastern (MID) AF: 0.0418 AC: 241 AN: 5766

European-Non Finnish (NFE) AF: 0.0102 AC: 11291 AN: 1111994

Other (OTH) AF: 0.0309 AC: 1869 AN: 60394

GnomAD4 genome AF: 0.0179 AC: 2725 AN: 152166 Hom.: 144 Cov.: 32 AF XY: 0.0206 AC XY: 1531 AN XY: 74404

African (AFR) AF: 0.00426 AC: 177 AN: 41514

American (AMR) AF: 0.0173 AC: 264 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 31 AN: 3470

East Asian (EAS) AF: 0.137 AC: 708 AN: 5164

South Asian (SAS) AF: 0.174 AC: 837 AN: 4808

European-Finnish (FIN) AF: 0.00368 AC: 39 AN: 10610

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00915 AC: 622 AN: 67990

Other (OTH) AF: 0.0180 AC: 38 AN: 2108

Alfa AF: 0.0151 Hom.: 202

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: 4893

Asia WGS AF: 0.145 AC: 502 AN: 3478

EpiCase AF: 0.0103

EpiControl AF: 0.0104

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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: 8421103, 20981092, 10566675, 19344888)

not specified Benign:2

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

Laron-type isolated somatotropin defect Benign:2

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as a Benign - Stand Alone, for Laron syndrome, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.).

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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	7.5
DANN	Benign	0.88
DEOGEN2	Benign	0.31	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N
PhyloP100		-0.014
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.022
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.25	T
Polyphen		0.087	B
Vest4		0.052
MPC		0.077
ClinPred		0.00012	T
GERP RS		1.7
Varity_R		0.12
gMVP		0.13
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs6182; hg19: chr5-42718928; COSMIC: COSV107218833; COSMIC: COSV107218833;