5-42424171-AGTGTGTGTGTGTGTGTGTGTGTGTGTGT-AGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Variant names:

• chr5-42424171-A-AGTGTGTGTGTGT
• rs1158830359
• NM_000163.5:c.-12+253_-12+264dupGTGTGTGTGTGT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_000163.5(GHR):​c.-12+253_-12+264dupGTGTGTGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.023 (106 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.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0234 (2356/100528) while in subpopulation NFE AF = 0.0267 (1345/50372). AF 95% confidence interval is 0.0255. There are 106 homozygotes in GnomAd4. There are 1060 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 106 AR,Unknown,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHR	NM_000163.5	c.-12+253_-12+264dupGTGTGTGTGTGT		intron_variant	Intron 1 of 9	ENST00000230882.9	NP_000154.1
GHR	NM_001242460.2	c.-12+253_-12+264dupGTGTGTGTGTGT		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+217insGTGTGTGTGTGT		intron_variant	Intron 1 of 9	1	NM_000163.5	ENSP00000230882.4

Frequencies

GnomAD3 genomes AF: 0.0234 AC: 2354 AN: 100460 Hom.: 106 Cov.: 0

Gnomad AFR AF: 0.0219

Gnomad AMI AF: 0.0115

Gnomad AMR AF: 0.0230

Gnomad ASJ AF: 0.0229

Gnomad EAS AF: 0.0164

Gnomad SAS AF: 0.0177

Gnomad FIN AF: 0.00889

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0267

Gnomad OTH AF: 0.0230

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

GnomAD4 genome AF: 0.0234 AC: 2356 AN: 100528 Hom.: 106 Cov.: 0 AF XY: 0.0227 AC XY: 1060 AN XY: 46722

African (AFR) AF: 0.0219 AC: 530 AN: 24204

American (AMR) AF: 0.0230 AC: 238 AN: 10350

Ashkenazi Jewish (ASJ) AF: 0.0229 AC: 61 AN: 2658

East Asian (EAS) AF: 0.0162 AC: 52 AN: 3218

South Asian (SAS) AF: 0.0179 AC: 45 AN: 2520

European-Finnish (FIN) AF: 0.00889 AC: 44 AN: 4948

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 190

European-Non Finnish (NFE) AF: 0.0267 AC: 1345 AN: 50372

Other (OTH) AF: 0.0241 AC: 33 AN: 1370

Alfa AF: 0.00 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

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;