5-42424171-AGTGTGTGTGTGTGTGTGTGTGTGTGTGT-AGTGTGTGTGTGT

Variant names:

• chr5-42424171-AGTGTGTGTGTGTGTGT-A
• rs1158830359
• NM_000163.5:c.-12+249_-12+264delGTGTGTGTGTGTGTGT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_000163.5(GHR):​c.-12+249_-12+264delGTGTGTGTGTGTGTGT 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 DEL_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 0.00029 (0 hom., cov: 0)
• Consequence: GHR NM_000163.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.25
• 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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000288 (29/100580) while in subpopulation SAS AF = 0.00397 (10/2520). AF 95% confidence interval is 0.00215. There are 0 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHR	NM_000163.5	c.-12+249_-12+264delGTGTGTGTGTGTGTGT		intron_variant	Intron 1 of 9	ENST00000230882.9	NP_000154.1
GHR	NM_001242460.2	c.-12+249_-12+264delGTGTGTGTGTGTGTGT		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+217_-12+232delGTGTGTGTGTGTGTGT		intron_variant	Intron 1 of 9	1	NM_000163.5	ENSP00000230882.4

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 29 AN: 100512 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000124

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000870

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000619

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000992

Gnomad OTH AF: 0.00

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

GnomAD4 genome AF: 0.000288 AC: 29 AN: 100580 Hom.: 0 Cov.: 0 AF XY: 0.000406 AC XY: 19 AN XY: 46752

African (AFR) AF: 0.000124 AC: 3 AN: 24226

American (AMR) AF: 0.000869 AC: 9 AN: 10354

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2658

East Asian (EAS) AF: 0.000622 AC: 2 AN: 3218

South Asian (SAS) AF: 0.00397 AC: 10 AN: 2520

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4950

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

European-Non Finnish (NFE) AF: 0.0000992 AC: 5 AN: 50396

Other (OTH) AF: 0.00 AC: 0 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

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;