5-42423817-C-A

Variant names:

• chr5-42423817-C-A
• rs368929640
• NM_000163.5:c.-150C>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_000163.5(GHR):​c.-150C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000213 in 164,252 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (0 hom.)
• Consequence: GHR NM_000163.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.190
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 5-42423817-C-A is Benign according to our data. Variant chr5-42423817-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 907634.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000191 (29/151496) while in subpopulation SAS AF = 0.00605 (29/4792). AF 95% confidence interval is 0.00433. There are 1 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHR	NM_000163.5	c.-150C>A		5_prime_UTR_variant	Exon 1 of 10	ENST00000230882.9	NP_000154.1
GHR	NM_001242460.2	c.-150C>A		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.-150C>A		5_prime_UTR_variant	Exon 1 of 10	1	NM_000163.5	ENSP00000230882.4

Frequencies

GnomAD3 genomes AF: 0.000192 AC: 29 AN: 151384 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00605

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000470 AC: 6 AN: 12756 Hom.: 0 Cov.: 0 AF XY: 0.000421 AC XY: 4 AN XY: 9512

African (AFR) AF: 0.00 AC: 0 AN: 156

American (AMR) AF: 0.00 AC: 0 AN: 134

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 74

East Asian (EAS) AF: 0.00 AC: 0 AN: 450

South Asian (SAS) AF: 0.00578 AC: 6 AN: 1038

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 116

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 52

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 10236

Other (OTH) AF: 0.00 AC: 0 AN: 500

GnomAD4 genome AF: 0.000191 AC: 29 AN: 151496 Hom.: 1 Cov.: 32 AF XY: 0.000297 AC XY: 22 AN XY: 74012

African (AFR) AF: 0.00 AC: 0 AN: 41394

American (AMR) AF: 0.00 AC: 0 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5110

South Asian (SAS) AF: 0.00605 AC: 29 AN: 4792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10442

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67792

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

Asia WGS AF: 0.00407 AC: 14 AN: 3454

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Laron-type isolated somatotropin defect Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	13
DANN	Benign	0.86
PhyloP100		-0.19
PromoterAI		-0.013	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs368929640; hg19: chr5-42423919;