rs121909360

chr5-42699978-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Moderate PP5_Moderate

The NM_000163.5(GHR):c.594A>G(p.Glu198=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000414 in 1,449,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: GHR NM_000163.5 synonymous
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.647

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 Uncertain_significance. Variant got 4 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 5-42699978-A-G is Pathogenic according to our data. Variant chr5-42699978-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 8635.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GHR	NM_000163.5	c.594A>G	p.Glu198=	synonymous_variant	6/10	ENST00000230882.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GHR	ENST00000230882.9	c.594A>G	p.Glu198=	synonymous_variant	6/10	1	NM_000163.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 250634 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135458

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000872

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.00000414 AC: 6 AN: 1449718 Hom.: 0 Cov.: 27 AF XY: 0.00000415 AC XY: 3 AN XY: 722040

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000898

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000182

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Laron-type isolated somatotropin defect Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2002

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 30, 2023

For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in the activation of a cryptic splice site in exon 6 (PMID: 1284474). ClinVar contains an entry for this variant (Variation ID: 8635). This variant is also known as E180splice. This variant has been observed in individuals with Laron syndrome (PMID: 1284474, 2233903, 8504296, 24664892). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121909360, gnomAD 0.006%). This sequence change affects codon 198 of the GHR mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the GHR protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 8 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
Cadd	Benign	21
Dann	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.96		Position offset: 0
DS_DL_spliceai		0.31		Position offset: 24

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

Publications

LitVar

Other links and lift over

dbSNP: rs121909360; hg19: chr5-42700080;