5-42424171-AGTGTGTGTGTGTGTGTGTGTGTGTGTGT-AGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Variant names:

• chr5-42424171-A-AGT
• rs1158830359
• NM_000163.5:c.-12+263_-12+264dupGT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_000163.5(GHR):​c.-12+263_-12+264dupGT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.16 (1637 hom., cov: 0)
• Consequence: GHR NM_000163.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.21
• Publications: 0 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHR	NM_000163.5	c.-12+263_-12+264dupGT		intron_variant	Intron 1 of 9	ENST00000230882.9	NP_000154.1
GHR	NM_001242460.2	c.-12+263_-12+264dupGT		intron_variant	Intron 1 of 8		NP_001229389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GHR	ENST00000230882.9	c.-12+216_-12+217insGT		intron_variant	Intron 1 of 9	1	NM_000163.5	ENSP00000230882.4

Frequencies

GnomAD3 genomes AF: 0.162 AC: 16219 AN: 100280 Hom.: 1637 Cov.: 0

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.182

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.162

Gnomad EAS AF: 0.204

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.168

Gnomad MID AF: 0.162

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.163

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

GnomAD4 genome AF: 0.162 AC: 16230 AN: 100350 Hom.: 1637 Cov.: 0 AF XY: 0.160 AC XY: 7453 AN XY: 46630

African (AFR) AF: 0.161 AC: 3886 AN: 24184

American (AMR) AF: 0.147 AC: 1516 AN: 10296

Ashkenazi Jewish (ASJ) AF: 0.162 AC: 428 AN: 2650

East Asian (EAS) AF: 0.204 AC: 657 AN: 3214

South Asian (SAS) AF: 0.155 AC: 389 AN: 2516

European-Finnish (FIN) AF: 0.168 AC: 830 AN: 4930

Middle Eastern (MID) AF: 0.165 AC: 31 AN: 188

European-Non Finnish (NFE) AF: 0.162 AC: 8147 AN: 50310

Other (OTH) AF: 0.161 AC: 219 AN: 1364

Alfa AF: 0.100 Hom.: 144

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1158830359; hg19: chr5-42424273; COSMIC: COSV50122034; COSMIC: COSV50122034;