rs121909368

chr5-42699899-A-Cchr5-42699899-A-T

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.515A>C(p.Gln172Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,448,924 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Q172Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GHR NM_000163.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.24

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 hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000163.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• PP5: Variant 5-42699899-A-C is Pathogenic according to our data. Variant chr5-42699899-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 8645.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-42699899-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GHR	NM_000163.5	c.515A>C	p.Gln172Pro	missense_variant	6/10	ENST00000230882.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GHR	ENST00000230882.9	c.515A>C	p.Gln172Pro	missense_variant	6/10	1	NM_000163.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1448924 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 721604

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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

Alfa AF: 0.0000454 Hom.: 0

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

Dec 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D;D;.;D;D;D;D;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.5	M;M;.;M;M;M;M;.;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.5	N;.;.;.;.;.;.;N;.
REVEL	Pathogenic	0.84
Sift	Benign	0.067	T;.;.;.;.;.;.;T;.
Sift4G	Uncertain	0.0090	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;D;D;D;.;.
Vest4		0.86
MutPred		0.84		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;Gain of sheet (P = 0.0827);
MVP		0.97
MPC		0.33
ClinPred		0.93	D
GERP RS		4.7
Varity_R		0.95
gMVP		0.88

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: rs121909368; hg19: chr5-42700001;