5-42495733-A-C

Variant names:

• chr5-42495733-A-C
• rs2972392
• NM_000163.5:c.-11-70131A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000163.5(GHR):​c.-11-70131A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.441 in 151,922 control chromosomes in the GnomAD database, including 15,267 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 0.44 (15267 hom., cov: 32)
• Consequence: GHR NM_000163.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.185
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.5 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHR	NM_000163.5	MANE Select	c.-11-70131A>C		intron	N/A	NP_000154.1
	GHR	NM_001242399.2		c.11-70131A>C		intron	N/A	NP_001229328.1
	GHR	NM_001242400.2		c.-296-18347A>C		intron	N/A	NP_001229329.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHR	ENST00000230882.9	TSL:1 MANE Select	c.-11-70131A>C		intron	N/A	ENSP00000230882.4
	GHR	ENST00000620156.4	TSL:5	c.11-70131A>C		intron	N/A	ENSP00000483403.1
	GHR	ENST00000615111.4	TSL:5	c.-296-18347A>C		intron	N/A	ENSP00000478291.1

Frequencies

GnomAD3 genomes AF: 0.441 AC: 66934 AN: 151804 Hom.: 15261 Cov.: 32

Gnomad AFR AF: 0.506

Gnomad AMI AF: 0.587

Gnomad AMR AF: 0.439

Gnomad ASJ AF: 0.369

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.328

Gnomad FIN AF: 0.442

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.434

Gnomad OTH AF: 0.457

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

GnomAD4 genome AF: 0.441 AC: 66969 AN: 151922 Hom.: 15267 Cov.: 32 AF XY: 0.438 AC XY: 32497 AN XY: 74260

African (AFR) AF: 0.506 AC: 20962 AN: 41432

American (AMR) AF: 0.439 AC: 6688 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.369 AC: 1278 AN: 3462

East Asian (EAS) AF: 0.130 AC: 673 AN: 5170

South Asian (SAS) AF: 0.328 AC: 1583 AN: 4822

European-Finnish (FIN) AF: 0.442 AC: 4672 AN: 10564

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.434 AC: 29499 AN: 67918

Other (OTH) AF: 0.452 AC: 949 AN: 2100

Alfa AF: 0.449 Hom.: 2015

Bravo AF: 0.445

Asia WGS AF: 0.250 AC: 869 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	3.6
DANN	Benign	0.46
PhyloP100		-0.18
Mutation Taster		=100/0	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: rs2972392; hg19: chr5-42495835;