rs2940935

chr5-42486501-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
GHR	NM_000163.5	c.-12+62546C>T		intron_variant		ENST00000230882.9
GHR	NM_001242399.2	c.10+61903C>T		intron_variant
GHR	NM_001242400.2	c.-296-27579C>T		intron_variant
GHR	NM_001242401.4	c.-12+3172C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GHR	ENST00000230882.9	c.-12+62546C>T		intron_variant		1	NM_000163.5	P1
GHR	ENST00000615111.4	c.-296-27579C>T		intron_variant		5		P1
GHR	ENST00000620156.4	c.10+61903C>T		intron_variant		5
GHR	ENST00000513671.5	c.-12+61903C>T		intron_variant, NMD_transcript_variant		4

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

Gnomad4 AFR AF: 0.195

Gnomad4 AMR AF: 0.152

Gnomad4 ASJ AF: 0.231

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.156

Gnomad4 FIN AF: 0.0753

Gnomad4 NFE AF: 0.190

Gnomad4 OTH AF: 0.183

Alfa AF: 0.176 Hom.: 325

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs2940935; hg19: chr5-42486603;