chr5-42655251-C-G

Variant names:

• chr5-42655251-C-G
• rs4451056
• NM_000163.5:c.136+26148C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000163.5(GHR):​c.136+26148C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.847 in 152,070 control chromosomes in the GnomAD database, including 54,678 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.85 (54678 hom., cov: 31)
• Consequence: GHR NM_000163.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.187
• Publications: 3 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: 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)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHR	NM_000163.5	MANE Select	c.136+26148C>G		intron	N/A	NP_000154.1
	GHR	NM_001242399.2		c.157+26148C>G		intron	N/A	NP_001229328.1
	GHR	NM_001242400.2		c.136+26148C>G		intron	N/A	NP_001229329.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHR	ENST00000230882.9	TSL:1 MANE Select	c.136+26148C>G		intron	N/A	ENSP00000230882.4
	GHR	ENST00000620156.4	TSL:5	c.157+26148C>G		intron	N/A	ENSP00000483403.1
	GHR	ENST00000537449.5	TSL:5	c.136+26148C>G		intron	N/A	ENSP00000442206.2

Frequencies

GnomAD3 genomes AF: 0.847 AC: 128666 AN: 151952 Hom.: 54634 Cov.: 31

Gnomad AFR AF: 0.837

Gnomad AMI AF: 0.807

Gnomad AMR AF: 0.861

Gnomad ASJ AF: 0.909

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.934

Gnomad FIN AF: 0.791

Gnomad MID AF: 0.899

Gnomad NFE AF: 0.838

Gnomad OTH AF: 0.845

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.847 AC: 128769 AN: 152070 Hom.: 54678 Cov.: 31 AF XY: 0.848 AC XY: 63009 AN XY: 74316

African (AFR) AF: 0.837 AC: 34717 AN: 41474

American (AMR) AF: 0.861 AC: 13140 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.909 AC: 3155 AN: 3472

East Asian (EAS) AF: 0.997 AC: 5156 AN: 5174

South Asian (SAS) AF: 0.934 AC: 4503 AN: 4822

European-Finnish (FIN) AF: 0.791 AC: 8364 AN: 10570

Middle Eastern (MID) AF: 0.905 AC: 266 AN: 294

European-Non Finnish (NFE) AF: 0.838 AC: 56946 AN: 67978

Other (OTH) AF: 0.846 AC: 1788 AN: 2114

Alfa AF: 0.779 Hom.: 2282

Bravo AF: 0.851

Asia WGS AF: 0.963 AC: 3347 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.3
DANN	Benign	0.50
PhyloP100		0.19
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4451056; hg19: chr5-42655353;