rs6176

chr5-42718980-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000163.5(GHR):c.1473C>T(p.Ser491=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0236 in 1,611,654 control chromosomes in the GnomAD database, including 564 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (42 hom., cov: 32)
  • Exomes 𝑓: 0.024 (522 hom.)
• Consequence: GHR NM_000163.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.214

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 5-42718980-C-T is Benign according to our data. Variant chr5-42718980-C-T is described in ClinVar as [Benign]. Clinvar id is 255404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-42718980-C-T is described in Lovd as [Benign]. Variant chr5-42718980-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.214 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0583 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GHR	NM_000163.5	c.1473C>T	p.Ser491=	synonymous_variant	10/10	ENST00000230882.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GHR	ENST00000230882.9	c.1473C>T	p.Ser491=	synonymous_variant	10/10	1	NM_000163.5	P1

Frequencies

GnomAD3 genomes AF: 0.0208 AC: 3161 AN: 152056 Hom.: 42 Cov.: 32

Gnomad AFR AF: 0.00795

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.0268

Gnomad ASJ AF: 0.0398

Gnomad EAS AF: 0.0193

Gnomad SAS AF: 0.0238

Gnomad FIN AF: 0.0141

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0266

Gnomad OTH AF: 0.0273

GnomAD3 exomes AF: 0.0226 AC: 5657 AN: 250096 Hom.: 89 AF XY: 0.0240 AC XY: 3237 AN XY: 135116

Gnomad AFR exome AF: 0.00695

Gnomad AMR exome AF: 0.0162

Gnomad ASJ exome AF: 0.0451

Gnomad EAS exome AF: 0.0182

Gnomad SAS exome AF: 0.0294

Gnomad FIN exome AF: 0.0147

Gnomad NFE exome AF: 0.0250

Gnomad OTH exome AF: 0.0280

GnomAD4 exome AF: 0.0239 AC: 34875 AN: 1459480 Hom.: 522 Cov.: 34 AF XY: 0.0243 AC XY: 17651 AN XY: 725700

Gnomad4 AFR exome AF: 0.00886

Gnomad4 AMR exome AF: 0.0178

Gnomad4 ASJ exome AF: 0.0468

Gnomad4 EAS exome AF: 0.0240

Gnomad4 SAS exome AF: 0.0289

Gnomad4 FIN exome AF: 0.0148

Gnomad4 NFE exome AF: 0.0238

Gnomad4 OTH exome AF: 0.0255

GnomAD4 genome AF: 0.0208 AC: 3160 AN: 152174 Hom.: 42 Cov.: 32 AF XY: 0.0204 AC XY: 1517 AN XY: 74396

Gnomad4 AFR AF: 0.00793

Gnomad4 AMR AF: 0.0267

Gnomad4 ASJ AF: 0.0398

Gnomad4 EAS AF: 0.0193

Gnomad4 SAS AF: 0.0239

Gnomad4 FIN AF: 0.0141

Gnomad4 NFE AF: 0.0266

Gnomad4 OTH AF: 0.0270

Alfa AF: 0.0250 Hom.: 40

Bravo AF: 0.0208

Asia WGS AF: 0.0140 AC: 50 AN: 3478

EpiCase AF: 0.0263

EpiControl AF: 0.0312

ClinVar

Significance: Benign

Submissions summary: Benign:6

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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 01, 2020	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Laron-type isolated somatotropin defect Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Benign	8.2
Dann	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs6176; hg19: chr5-42719082; COSMIC: COSV50134809; COSMIC: COSV50134809;