NM_000163.5:c.-12+62546C>T

Variant names:

• chr5-42486501-C-T
• rs2940935
• NM_000163.5:c.-12+62546C>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.-12+62546C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 152,148 control chromosomes in the GnomAD database, including 2,563 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 0.17 (2563 hom., cov: 33)
• Consequence: GHR NM_000163.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.171
• Publications: 2 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.192 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHR	NM_000163.5	c.-12+62546C>T		intron_variant	Intron 1 of 9	ENST00000230882.9	NP_000154.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GHR	ENST00000230882.9	c.-12+62546C>T		intron_variant	Intron 1 of 9	1	NM_000163.5	ENSP00000230882.4
GHR	ENST00000620156.4	c.10+61903C>T		intron_variant	Intron 1 of 9	5		ENSP00000483403.1
GHR	ENST00000615111.4	c.-296-27579C>T		intron_variant	Intron 1 of 10	5		ENSP00000478291.1
GHR	ENST00000513671.5	n.-12+61903C>T		intron_variant	Intron 1 of 5	4		ENSP00000426739.1

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26443 AN: 152030 Hom.: 2562 Cov.: 33

Gnomad AFR AF: 0.195

Gnomad AMI AF: 0.339

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.0753

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.190

Gnomad OTH AF: 0.186

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

GnomAD4 genome AF: 0.174 AC: 26444 AN: 152148 Hom.: 2563 Cov.: 33 AF XY: 0.167 AC XY: 12432 AN XY: 74364

African (AFR) AF: 0.195 AC: 8094 AN: 41494

American (AMR) AF: 0.152 AC: 2319 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.231 AC: 803 AN: 3470

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5170

South Asian (SAS) AF: 0.156 AC: 754 AN: 4820

European-Finnish (FIN) AF: 0.0753 AC: 796 AN: 10572

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.190 AC: 12902 AN: 68010

Other (OTH) AF: 0.183 AC: 387 AN: 2110

Alfa AF: 0.176 Hom.: 340

Bravo AF: 0.181

Asia WGS AF: 0.0730 AC: 255 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.4
DANN	Benign	0.72
PhyloP100		-0.17
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: rs2940935; hg19: chr5-42486603;