chr5-42564646-G-T

Variant names:

• chr5-42564646-G-T
• rs6883523
• NM_000163.5:c.-11-1218G>T

Variant summary

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

The NM_000163.5(GHR):​c.-11-1218G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 152,086 control chromosomes in the GnomAD database, including 2,604 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 0.18 (2604 hom., cov: 32)
• Consequence: GHR NM_000163.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.664
• Publications: 7 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 = 0.191 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHR	NM_000163.5	MANE Select	c.-11-1218G>T		intron	N/A	NP_000154.1
	GHR	NM_001242399.2		c.11-1218G>T		intron	N/A	NP_001229328.1
	GHR	NM_001242400.2		c.-11-1218G>T		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.-11-1218G>T		intron	N/A	ENSP00000230882.4
	GHR	ENST00000620156.4	TSL:5	c.11-1218G>T		intron	N/A	ENSP00000483403.1
	GHR	ENST00000537449.5	TSL:5	c.-11-1218G>T		intron	N/A	ENSP00000442206.2

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26787 AN: 151968 Hom.: 2601 Cov.: 32

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.138

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0704

Gnomad FIN AF: 0.289

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.194

Gnomad OTH AF: 0.175

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

GnomAD4 genome AF: 0.176 AC: 26799 AN: 152086 Hom.: 2604 Cov.: 32 AF XY: 0.178 AC XY: 13242 AN XY: 74348

African (AFR) AF: 0.172 AC: 7119 AN: 41502

American (AMR) AF: 0.138 AC: 2108 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 383 AN: 3466

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5176

South Asian (SAS) AF: 0.0703 AC: 339 AN: 4824

European-Finnish (FIN) AF: 0.289 AC: 3053 AN: 10560

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.194 AC: 13162 AN: 67962

Other (OTH) AF: 0.174 AC: 367 AN: 2110

Alfa AF: 0.178 Hom.: 8021

Bravo AF: 0.165

Asia WGS AF: 0.0420 AC: 150 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.073
DANN	Benign	0.53
PhyloP100		-0.66
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: rs6883523; hg19: chr5-42564748; COSMIC: COSV50112597; COSMIC: COSV50112597;