5-42629069-G-A

Variant names:

• chr5-42629069-G-A
• rs121909370
• NM_000163.5:c.102G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000163.5(GHR):​c.102G>A​(p.Trp34*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 21)
• Consequence: GHR NM_000163.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.0770
• Publications: 2 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• short stature due to partial GHR deficiency

  Inheritance: AD, Unknown Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-42629069-G-A is Pathogenic according to our data. Variant chr5-42629069-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 8657.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHR	NM_000163.5	MANE Select	c.102G>A	p.Trp34*	stop_gained	Exon 3 of 10	NP_000154.1	P10912-1
	GHR	NM_001242399.2		c.123G>A	p.Trp41*	stop_gained	Exon 3 of 10	NP_001229328.1	A0A087X0H5
	GHR	NM_001242400.2		c.102G>A	p.Trp34*	stop_gained	Exon 4 of 11	NP_001229329.1	P10912-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHR	ENST00000230882.9	TSL:1 MANE Select	c.102G>A	p.Trp34*	stop_gained	Exon 3 of 10	ENSP00000230882.4	P10912-1
	GHR	ENST00000620156.4	TSL:5	c.123G>A	p.Trp41*	stop_gained	Exon 3 of 10	ENSP00000483403.1	A0A087X0H5
	GHR	ENST00000537449.5	TSL:5	c.102G>A	p.Trp34*	stop_gained	Exon 3 of 10	ENSP00000442206.2	P10912-1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 21

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Growth hormone insensitivity syndrome (1)
1	-	-	Laron-type isolated somatotropin defect (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	31
DANN	Uncertain	0.99
Eigen	Uncertain	0.47
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.071	N
PhyloP100		0.077
Vest4		0.85
GERP RS		2.4
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs121909370; hg19: chr5-42629171;