5-42626104-T-C

Variant names:

• chr5-42626104-T-C
• rs4590183
• NM_000163.5:c.71-2934T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000163.5(GHR):​c.71-2934T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.33 in 151,972 control chromosomes in the GnomAD database, including 9,288 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 0.33 (9288 hom., cov: 31)
• Consequence: GHR NM_000163.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.25
• Publications: 9 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=-1.04).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.502 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHR	NM_000163.5	c.71-2934T>C		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.71-2934T>C		intron_variant	Intron 2 of 9	1	NM_000163.5	ENSP00000230882.4

Frequencies

GnomAD3 genomes AF: 0.330 AC: 50065 AN: 151854 Hom.: 9259 Cov.: 31

Gnomad AFR AF: 0.507

Gnomad AMI AF: 0.386

Gnomad AMR AF: 0.265

Gnomad ASJ AF: 0.264

Gnomad EAS AF: 0.181

Gnomad SAS AF: 0.252

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.332

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

GnomAD4 genome AF: 0.330 AC: 50138 AN: 151972 Hom.: 9288 Cov.: 31 AF XY: 0.324 AC XY: 24107 AN XY: 74308

African (AFR) AF: 0.508 AC: 21011 AN: 41400

American (AMR) AF: 0.265 AC: 4052 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 914 AN: 3468

East Asian (EAS) AF: 0.180 AC: 927 AN: 5156

South Asian (SAS) AF: 0.252 AC: 1214 AN: 4822

European-Finnish (FIN) AF: 0.258 AC: 2735 AN: 10592

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.267 AC: 18145 AN: 67938

Other (OTH) AF: 0.329 AC: 695 AN: 2110

Alfa AF: 0.288 Hom.: 21184

Bravo AF: 0.341

Asia WGS AF: 0.222 AC: 773 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.53
DANN	Benign	0.26
PhyloP100		-2.3
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: rs4590183; hg19: chr5-42626206;