5-42623143-T-C

Variant names:

• chr5-42623143-T-C
• rs4292454
• NM_000163.5:c.71-5895T>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.71-5895T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.475 in 152,020 control chromosomes in the GnomAD database, including 19,139 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 0.47 (19139 hom., cov: 32)
• Consequence: GHR NM_000163.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.806
• 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.687 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHR	NM_000163.5	c.71-5895T>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.71-5895T>C		intron_variant	Intron 2 of 9	1	NM_000163.5	ENSP00000230882.4

Frequencies

GnomAD3 genomes AF: 0.475 AC: 72119 AN: 151902 Hom.: 19136 Cov.: 32

Gnomad AFR AF: 0.694

Gnomad AMI AF: 0.547

Gnomad AMR AF: 0.380

Gnomad ASJ AF: 0.459

Gnomad EAS AF: 0.00597

Gnomad SAS AF: 0.253

Gnomad FIN AF: 0.381

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.428

Gnomad OTH AF: 0.478

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

GnomAD4 genome AF: 0.475 AC: 72148 AN: 152020 Hom.: 19139 Cov.: 32 AF XY: 0.466 AC XY: 34640 AN XY: 74322

African (AFR) AF: 0.694 AC: 28744 AN: 41438

American (AMR) AF: 0.379 AC: 5795 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.459 AC: 1593 AN: 3470

East Asian (EAS) AF: 0.00599 AC: 31 AN: 5178

South Asian (SAS) AF: 0.251 AC: 1211 AN: 4818

European-Finnish (FIN) AF: 0.381 AC: 4026 AN: 10578

Middle Eastern (MID) AF: 0.545 AC: 159 AN: 292

European-Non Finnish (NFE) AF: 0.428 AC: 29092 AN: 67950

Other (OTH) AF: 0.473 AC: 998 AN: 2112

Alfa AF: 0.406 Hom.: 7792

Bravo AF: 0.485

Asia WGS AF: 0.156 AC: 548 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.096
DANN	Benign	0.70
PhyloP100		-0.81
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: rs4292454; hg19: chr5-42623245;