5-42711314-G-C

Variant names:

• chr5-42711314-G-C
• rs45588036
• NM_000163.5:c.726G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1 BP4

The NM_000163.5(GHR):​c.726G>C​(p.Glu242Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000583 in 1,613,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000059 (0 hom.)
• Consequence: GHR NM_000163.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:1
• Conservation: PhyloP100: 0.0170

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 1 ACMG points.

• PM1: In a strand (size 3) in uniprot entity GHR_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000163.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.34135565).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHR	NM_000163.5	c.726G>C	p.Glu242Asp	missense_variant	Exon 7 of 10	ENST00000230882.9	NP_000154.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GHR	ENST00000230882.9	c.726G>C	p.Glu242Asp	missense_variant	Exon 7 of 10	1	NM_000163.5	ENSP00000230882.4

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251374 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135854

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000589 AC: 86 AN: 1460884 Hom.: 0 Cov.: 30 AF XY: 0.0000592 AC XY: 43 AN XY: 726832

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: 0.0000720

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74326

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Short stature due to partial GHR deficiency Pathogenic:1 Uncertain:1

May 17, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS4_SUP -

Oct 26, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Benign:1

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	10
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;T;.;T;T;T;T;.;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.68
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.77	.;.;T;.;.;T;.;T;T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.34	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	1.7	L;L;.;L;L;L;L;.;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.3	N;.;.;.;.;.;.;N;.
REVEL	Uncertain	0.61
Sift	Uncertain	0.013	D;.;.;.;.;.;.;D;.
Sift4G	Benign	0.17	T;T;T;T;T;T;T;T;T
Polyphen		0.016	B;B;.;B;B;B;B;.;.
Vest4		0.63
MutPred		0.72		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		0.89
MPC		0.044
ClinPred		0.14	T
GERP RS		-0.95
Varity_R		0.47
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs45588036; hg19: chr5-42711416;