chr5-42424171-A-AGTGTGTGTGTGTGTGTGT

Variant names:

• chr5-42424171-A-AGTGTGTGTGTGTGTGTGT
• rs1158830359
• NM_000163.5:c.-12+247_-12+264dupGTGTGTGTGTGTGTGTGT

Variant summary

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

The NM_000163.5(GHR):​c.-12+247_-12+264dupGTGTGTGTGTGTGTGTGT 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 0.0016 (6 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• short stature due to partial GHR deficiency

  Inheritance: AD, Unknown Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00156 (157/100580) while in subpopulation AFR AF = 0.00223 (54/24224). AF 95% confidence interval is 0.00175. There are 6 homozygotes in GnomAd4. There are 75 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR,Unknown,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHR	NM_000163.5	MANE Select	c.-12+247_-12+264dupGTGTGTGTGTGTGTGTGT		intron	N/A	NP_000154.1	P10912-1
	GHR	NM_001242460.2		c.-12+247_-12+264dupGTGTGTGTGTGTGTGTGT		intron	N/A	NP_001229389.1	P10912-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHR	ENST00000230882.9	TSL:1 MANE Select	c.-12+216_-12+217insGTGTGTGTGTGTGTGTGT		intron	N/A	ENSP00000230882.4	P10912-1
	GHR	ENST00000887685.1		c.-368+216_-368+217insGTGTGTGTGTGTGTGTGT		intron	N/A	ENSP00000557744.1
	GHR	ENST00000887687.1		c.-105+216_-105+217insGTGTGTGTGTGTGTGTGT		intron	N/A	ENSP00000557746.1

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 157 AN: 100512 Hom.: 6 Cov.: 0

Gnomad AFR AF: 0.00224

Gnomad AMI AF: 0.00287

Gnomad AMR AF: 0.000387

Gnomad ASJ AF: 0.00113

Gnomad EAS AF: 0.000928

Gnomad SAS AF: 0.000789

Gnomad FIN AF: 0.00101

Gnomad MID AF: 0.00500

Gnomad NFE AF: 0.00157

Gnomad OTH AF: 0.00297

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

GnomAD4 genome AF: 0.00156 AC: 157 AN: 100580 Hom.: 6 Cov.: 0 AF XY: 0.00160 AC XY: 75 AN XY: 46754

African (AFR) AF: 0.00223 AC: 54 AN: 24224

American (AMR) AF: 0.000386 AC: 4 AN: 10354

Ashkenazi Jewish (ASJ) AF: 0.00113 AC: 3 AN: 2658

East Asian (EAS) AF: 0.000932 AC: 3 AN: 3218

South Asian (SAS) AF: 0.000794 AC: 2 AN: 2520

European-Finnish (FIN) AF: 0.00101 AC: 5 AN: 4950

Middle Eastern (MID) AF: 0.00526 AC: 1 AN: 190

European-Non Finnish (NFE) AF: 0.00157 AC: 79 AN: 50398

Other (OTH) AF: 0.00292 AC: 4 AN: 1370

Alfa AF: 0.00 Hom.: 144

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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;