5-42617390-A-G

Variant names:

• chr5-42617390-A-G
• rs4866941
• NM_000163.5:c.71-11648A>G

Variant summary

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

The NM_001242399.2(GHR):​c.92-11648A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. 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 0.13 (10 hom., cov: 0)
• Consequence: GHR NM_001242399.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.211
• 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=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.202 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001242399.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHR	NM_000163.5	MANE Select	c.71-11648A>G		intron	N/A	NP_000154.1
	GHR	NM_001242399.2		c.92-11648A>G		intron	N/A	NP_001229328.1
	GHR	NM_001242400.2		c.71-11648A>G		intron	N/A	NP_001229329.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHR	ENST00000230882.9	TSL:1 MANE Select	c.71-11648A>G		intron	N/A	ENSP00000230882.4
	GHR	ENST00000620156.4	TSL:5	c.92-11648A>G		intron	N/A	ENSP00000483403.1
	GHR	ENST00000537449.5	TSL:5	c.71-11648A>G		intron	N/A	ENSP00000442206.2

Frequencies

GnomAD3 genomes AF: 0.134 AC: 914 AN: 6806 Hom.: 9 Cov.: 0

Gnomad AFR AF: 0.0510

Gnomad AMI AF: 0.396

Gnomad AMR AF: 0.0547

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.0407

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.215

Gnomad OTH AF: 0.111

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

GnomAD4 genome AF: 0.134 AC: 915 AN: 6822 Hom.: 10 Cov.: 0 AF XY: 0.121 AC XY: 384 AN XY: 3164

African (AFR) AF: 0.0505 AC: 116 AN: 2298

American (AMR) AF: 0.0539 AC: 29 AN: 538

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 42

East Asian (EAS) AF: 0.115 AC: 20 AN: 174

South Asian (SAS) AF: 0.197 AC: 24 AN: 122

European-Finnish (FIN) AF: 0.0407 AC: 14 AN: 344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 6

European-Non Finnish (NFE) AF: 0.215 AC: 683 AN: 3174

Other (OTH) AF: 0.132 AC: 10 AN: 76

Alfa AF: 0.703 Hom.: 56411

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.21
DANN	Benign	0.70
PhyloP100		-0.21
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: rs4866941; hg19: chr5-42617492; COSMIC: COSV50108963;