rs2940944

Positions:

• chr5-42489040-A-C
• chr5-42489040-A-G
• chr5-42489040-A-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+65085A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.466 in 151,696 control chromosomes in the GnomAD database, including 16,920 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 (16920 hom., cov: 31)
• Consequence: GHR NM_000163.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0530

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 = 0.506 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GHR	NM_000163.5	c.-12+65085A>C		intron_variant		ENST00000230882.9	NP_000154.1
GHR	NM_001242399.2	c.10+64442A>C		intron_variant			NP_001229328.1
GHR	NM_001242400.2	c.-296-25040A>C		intron_variant			NP_001229329.1
GHR	NM_001242401.4	c.-12+5711A>C		intron_variant			NP_001229330.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GHR	ENST00000230882.9	c.-12+65085A>C		intron_variant		1	NM_000163.5	ENSP00000230882	P1
GHR	ENST00000615111.4	c.-296-25040A>C		intron_variant		5		ENSP00000478291	P1
GHR	ENST00000620156.4	c.10+64442A>C		intron_variant		5		ENSP00000483403
GHR	ENST00000513671.5	c.-12+64442A>C		intron_variant, NMD_transcript_variant		4		ENSP00000426739

Frequencies

GnomAD3 genomes AF: 0.466 AC: 70602 AN: 151578 Hom.: 16920 Cov.: 31

Gnomad AFR AF: 0.512

Gnomad AMI AF: 0.589

Gnomad AMR AF: 0.467

Gnomad ASJ AF: 0.469

Gnomad EAS AF: 0.132

Gnomad SAS AF: 0.361

Gnomad FIN AF: 0.456

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.469

Gnomad OTH AF: 0.494

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

GnomAD4 genome AF: 0.466 AC: 70625 AN: 151696 Hom.: 16920 Cov.: 31 AF XY: 0.462 AC XY: 34213 AN XY: 74100

Gnomad4 AFR AF: 0.512

Gnomad4 AMR AF: 0.467

Gnomad4 ASJ AF: 0.469

Gnomad4 EAS AF: 0.132

Gnomad4 SAS AF: 0.360

Gnomad4 FIN AF: 0.456

Gnomad4 NFE AF: 0.469

Gnomad4 OTH AF: 0.489

Alfa AF: 0.460 Hom.: 24219

Bravo AF: 0.470

Asia WGS AF: 0.257 AC: 895 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	2.8
DANN	Benign	0.34

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: rs2940944; hg19: chr5-42489142;