5-42424598-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000163.5(GHR):c.-12+643G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GHR NM_000163.5 intron
• Scores: Splicing: ADA: 0.02141
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.213

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18665597).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GHR	NM_000163.5	c.-12+643G>A		intron_variant		ENST00000230882.9
GHR	NM_001242399.2	c.10G>A	p.Gly4Ser	missense_variant, splice_region_variant	1/10
GHR	NM_001242400.2	c.-297G>A		splice_region_variant, 5_prime_UTR_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GHR	ENST00000230882.9	c.-12+643G>A		intron_variant		1	NM_000163.5	P1
GHR	ENST00000620156.4	c.10G>A	p.Gly4Ser	missense_variant, splice_region_variant	1/10	5
GHR	ENST00000615111.4	c.-297G>A		splice_region_variant, 5_prime_UTR_variant	1/11	5		P1
GHR	ENST00000513671.5	c.-12G>A		splice_region_variant, 5_prime_UTR_variant, NMD_transcript_variant	1/6	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Short stature due to partial GHR deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Dec 04, 2019

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,BP4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	6.3
Dann	Benign	0.86
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.30	T
MetaRNN	Benign	0.19	T
MutationTaster	Benign	1.0	N;N
Vest4		0.23
MVP		0.64
GERP RS		-1.8
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.021
dbscSNV1_RF	Benign	0.43
SpliceAI score (max)		0.13		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: rs1742761582; hg19: chr5-42424700;