dbSNP rs121909371: GHR:p.Cys101* (chr5-42694953-C-A) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_000163.5(GHR):c.303C>A(p.Cys101*) 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: 32)

Consequence

GHR
NM_000163.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: -0.191

Publications

4 publications found

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 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)

GHR links:

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ACMG classification

Classification was made for transcript

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 5-42694953-C-A is Pathogenic according to our data. Variant chr5-42694953-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 8659.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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GHR	NM_000163.5	MANE Select	c.303C>A	p.Cys101*	stop_gained	Exon 5 of 10	NP_000154.1
GHR	NM_001242399.2		c.324C>A	p.Cys108*	stop_gained	Exon 5 of 10	NP_001229328.1
GHR	NM_001242400.2		c.303C>A	p.Cys101*	stop_gained	Exon 6 of 11	NP_001229329.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GHR	ENST00000230882.9	TSL:1 MANE Select	c.303C>A	p.Cys101*	stop_gained	Exon 5 of 10	ENSP00000230882.4
GHR	ENST00000620156.4	TSL:5	c.324C>A	p.Cys108*	stop_gained	Exon 5 of 10	ENSP00000483403.1
GHR	ENST00000537449.5	TSL:5	c.303C>A	p.Cys101*	stop_gained	Exon 5 of 10	ENSP00000442206.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000273

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Laron-type isolated somatotropin defect

Pathogenic:1

Jan 01, 2005

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

not provided

Pathogenic:1

Feb 21, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.C83X (c.346C>A) using alternative nomenclature; This variant is associated with the following publications: (PMID: 25525159, 28498917, 19169479, 29748515, 17405847, 21525302, 15536163)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Benign

0.19

Eigen_PC

Benign

-0.024

FATHMM_MKL

Benign

0.76

PhyloP100

-0.19

Vest4

0.88

GERP RS

-0.93

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over