chr5-42423803-A-G

Variant names:

• chr5-42423803-A-G
• rs2940928
• NM_000163.5:c.-164A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000163.5(GHR):​c.-164A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.823 in 164,420 control chromosomes in the GnomAD database, including 55,987 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (51557 hom., cov: 34)
  • Exomes 𝑓: 0.84 (4430 hom.)
• Consequence: GHR NM_000163.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.624
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 5-42423803-A-G is Benign according to our data. Variant chr5-42423803-A-G is described in ClinVar as [Benign]. Clinvar id is 353676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHR	NM_000163.5	c.-164A>G		5_prime_UTR_variant	Exon 1 of 10	ENST00000230882.9	NP_000154.1
GHR	NM_001242460.2	c.-164A>G		5_prime_UTR_variant	Exon 1 of 9		NP_001229389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GHR	ENST00000230882.9	c.-164A>G		5_prime_UTR_variant	Exon 1 of 10	1	NM_000163.5	ENSP00000230882.4

Frequencies

GnomAD3 genomes AF: 0.822 AC: 124734 AN: 151728 Hom.: 51507 Cov.: 34

Gnomad AFR AF: 0.800

Gnomad AMI AF: 0.776

Gnomad AMR AF: 0.840

Gnomad ASJ AF: 0.770

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.850

Gnomad FIN AF: 0.922

Gnomad MID AF: 0.723

Gnomad NFE AF: 0.805

Gnomad OTH AF: 0.804

GnomAD4 exome AF: 0.836 AC: 10527 AN: 12586 Hom.: 4430 Cov.: 0 AF XY: 0.834 AC XY: 7787 AN XY: 9342

African (AFR) AF: 0.810 AC: 136 AN: 168

American (AMR) AF: 0.866 AC: 142 AN: 164

Ashkenazi Jewish (ASJ) AF: 0.720 AC: 59 AN: 82

East Asian (EAS) AF: 1.00 AC: 470 AN: 470

South Asian (SAS) AF: 0.867 AC: 896 AN: 1034

European-Finnish (FIN) AF: 0.947 AC: 125 AN: 132

Middle Eastern (MID) AF: 0.700 AC: 35 AN: 50

European-Non Finnish (NFE) AF: 0.825 AC: 8261 AN: 10012

Other (OTH) AF: 0.850 AC: 403 AN: 474

GnomAD4 genome AF: 0.822 AC: 124836 AN: 151834 Hom.: 51557 Cov.: 34 AF XY: 0.829 AC XY: 61523 AN XY: 74208

African (AFR) AF: 0.800 AC: 33172 AN: 41472

American (AMR) AF: 0.840 AC: 12826 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.770 AC: 2674 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5138 AN: 5144

South Asian (SAS) AF: 0.850 AC: 4092 AN: 4814

European-Finnish (FIN) AF: 0.922 AC: 9684 AN: 10502

Middle Eastern (MID) AF: 0.729 AC: 210 AN: 288

European-Non Finnish (NFE) AF: 0.805 AC: 54644 AN: 67872

Other (OTH) AF: 0.806 AC: 1690 AN: 2096

Alfa AF: 0.819 Hom.: 6368

Bravo AF: 0.814

Asia WGS AF: 0.928 AC: 3179 AN: 3426

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 11, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Laron-type isolated somatotropin defect Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	13
DANN	Benign	0.68
PhyloP100		-0.62
PromoterAI		0.029	Neutral
Mutation Taster		=296/4	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: rs2940928; hg19: chr5-42423905;