chr5-42423791-A-G

Variant names:

• chr5-42423791-A-G
• rs1314535276
• NM_000163.5:c.-176A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000163.5(GHR):​c.-176A>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 0.0000366 in 163,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000083 (0 hom.)
• Consequence: GHR NM_000163.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.32
• 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, G2P, Labcorp Genetics (formerly Invitae)
• short stature due to partial GHR deficiency

  Inheritance: AD, Unknown Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000163.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHR	NM_000163.5	MANE Select	c.-176A>G		5_prime_UTR	Exon 1 of 10	NP_000154.1	P10912-1
	GHR	NM_001242460.2		c.-176A>G		5_prime_UTR	Exon 1 of 9	NP_001229389.1	P10912-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHR	ENST00000230882.9	TSL:1 MANE Select	c.-176A>G		5_prime_UTR	Exon 1 of 10	ENSP00000230882.4	P10912-1
	GHR	ENST00000887685.1		c.-532A>G		5_prime_UTR	Exon 1 of 13	ENSP00000557744.1
	GHR	ENST00000887687.1		c.-269A>G		5_prime_UTR	Exon 1 of 11	ENSP00000557746.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151836 Hom.: 0 Cov.: 33

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: 0.00

Gnomad FIN AF: 0.000475

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000832 AC: 1 AN: 12018 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 8876

African (AFR) AF: 0.00 AC: 0 AN: 162

American (AMR) AF: 0.00 AC: 0 AN: 170

Ashkenazi Jewish (ASJ) AF: 0.0114 AC: 1 AN: 88

East Asian (EAS) AF: 0.00 AC: 0 AN: 444

South Asian (SAS) AF: 0.00 AC: 0 AN: 1026

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 134

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 9502

Other (OTH) AF: 0.00 AC: 0 AN: 440

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151836 Hom.: 0 Cov.: 33 AF XY: 0.0000270 AC XY: 2 AN XY: 74160

African (AFR) AF: 0.00 AC: 0 AN: 41370

American (AMR) AF: 0.00 AC: 0 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000475 AC: 5 AN: 10528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67914

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000843 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Laron-type isolated somatotropin defect (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.2
DANN	Benign	0.36
PhyloP100		-1.3
PromoterAI		-0.015	Neutral

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: rs1314535276; hg19: chr5-42423893;