rs6898743

Variant names:

• chr5-42602390-C-G
• rs6898743
• NM_000163.5:c.71-26648C>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.71-26648C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.776 in 152,078 control chromosomes in the GnomAD database, including 46,479 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 0.78 (46479 hom., cov: 31)
• Consequence: GHR NM_000163.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0340
• Publications: 11 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=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.866 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHR	NM_000163.5	c.71-26648C>G		intron_variant	Intron 2 of 9	ENST00000230882.9	NP_000154.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GHR	ENST00000230882.9	c.71-26648C>G		intron_variant	Intron 2 of 9	1	NM_000163.5	ENSP00000230882.4

Frequencies

GnomAD3 genomes AF: 0.776 AC: 117990 AN: 151960 Hom.: 46443 Cov.: 31

Gnomad AFR AF: 0.873

Gnomad AMI AF: 0.841

Gnomad AMR AF: 0.742

Gnomad ASJ AF: 0.804

Gnomad EAS AF: 0.383

Gnomad SAS AF: 0.620

Gnomad FIN AF: 0.777

Gnomad MID AF: 0.747

Gnomad NFE AF: 0.764

Gnomad OTH AF: 0.764

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

GnomAD4 genome AF: 0.776 AC: 118086 AN: 152078 Hom.: 46479 Cov.: 31 AF XY: 0.773 AC XY: 57434 AN XY: 74318

African (AFR) AF: 0.873 AC: 36238 AN: 41506

American (AMR) AF: 0.742 AC: 11338 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.804 AC: 2792 AN: 3472

East Asian (EAS) AF: 0.384 AC: 1982 AN: 5164

South Asian (SAS) AF: 0.619 AC: 2984 AN: 4818

European-Finnish (FIN) AF: 0.777 AC: 8219 AN: 10582

Middle Eastern (MID) AF: 0.748 AC: 220 AN: 294

European-Non Finnish (NFE) AF: 0.764 AC: 51935 AN: 67940

Other (OTH) AF: 0.762 AC: 1611 AN: 2114

Alfa AF: 0.782 Hom.: 5805

Bravo AF: 0.778

Asia WGS AF: 0.508 AC: 1771 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.65
DANN	Benign	0.63
PhyloP100		-0.034
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: rs6898743; hg19: chr5-42602492;