5-42694985-G-C

Position:

• chr5-42694985-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000163.5(GHR):​c.335G>C​(p.Cys112Ser) variant causes a missense change involving the alteration of a 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 (no stars). Synonymous variant affecting the same amino acid position (i.e. C112C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GHR NM_000163.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.33

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a topological_domain Extracellular (size 245) in uniprot entity GHR_HUMAN there are 39 pathogenic changes around while only 4 benign (91%) in NM_000163.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 5-42694985-G-C is Pathogenic according to our data. Variant chr5-42694985-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 8662.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-42694985-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GHR	NM_000163.5	c.335G>C	p.Cys112Ser	missense_variant	5/10	ENST00000230882.9	NP_000154.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GHR	ENST00000230882.9	c.335G>C	p.Cys112Ser	missense_variant	5/10	1	NM_000163.5	ENSP00000230882.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Laron-type isolated somatotropin defect Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D;D;.;D;D;D;D;.;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;.;D;.;.;D;.;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	3.5	M;M;.;M;M;M;M;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-4.7	D;.;.;.;.;.;.;D;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;D;D;D;.;.
Vest4		0.95
MutPred		0.96		Gain of disorder (P = 3e-04);Gain of disorder (P = 3e-04);.;Gain of disorder (P = 3e-04);Gain of disorder (P = 3e-04);Gain of disorder (P = 3e-04);Gain of disorder (P = 3e-04);.;Gain of disorder (P = 3e-04);
MVP		0.99
MPC		0.35
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.99
gMVP		0.98

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

LitVar

Other links and lift over

dbSNP: rs121909372; hg19: chr5-42695087;