5-42699868-G-A

Variant names:

• chr5-42699868-G-A
• rs6413484
• NM_000163.5:c.484G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_000163.5(GHR):​c.484G>A​(p.Val162Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000782 in 1,610,894 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V162F) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0043 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00041 (8 hom.)
• Consequence: GHR NM_000163.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:3
• Conservation: PhyloP100: 1.33
• Publications: 13 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: G2P, Orphanet, 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: Benign. The variant received -11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000163.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.008785516).
• BP6: Variant 5-42699868-G-A is Benign according to our data. Variant chr5-42699868-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 8652.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00431 (656/152272) while in subpopulation AFR AF = 0.0137 (570/41550). AF 95% confidence interval is 0.0128. There are 8 homozygotes in GnomAd4. There are 299 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR,Unknown,AD gene

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.484G>A	p.Val162Ile	missense	Exon 6 of 10	NP_000154.1	P10912-1
	GHR	NM_001242399.2		c.505G>A	p.Val169Ile	missense	Exon 6 of 10	NP_001229328.1	A0A087X0H5
	GHR	NM_001242400.2		c.484G>A	p.Val162Ile	missense	Exon 7 of 11	NP_001229329.1	P10912-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHR	ENST00000230882.9	TSL:1 MANE Select	c.484G>A	p.Val162Ile	missense	Exon 6 of 10	ENSP00000230882.4	P10912-1
	GHR	ENST00000620156.4	TSL:5	c.505G>A	p.Val169Ile	missense	Exon 6 of 10	ENSP00000483403.1	A0A087X0H5
	GHR	ENST00000537449.5	TSL:5	c.484G>A	p.Val162Ile	missense	Exon 6 of 10	ENSP00000442206.2	P10912-1

Frequencies

GnomAD3 genomes AF: 0.00431 AC: 656 AN: 152154 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00426

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00106 AC: 267 AN: 250980 AF XY: 0.000737

Gnomad AFR exome AF: 0.0132

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000414 AC: 604 AN: 1458622 Hom.: 8 Cov.: 28 AF XY: 0.000355 AC XY: 258 AN XY: 725864

African (AFR) AF: 0.0114 AC: 381 AN: 33396

American (AMR) AF: 0.00163 AC: 73 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39666

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5762

European-Non Finnish (NFE) AF: 0.0000469 AC: 52 AN: 1109162

Other (OTH) AF: 0.00129 AC: 78 AN: 60266

GnomAD4 genome AF: 0.00431 AC: 656 AN: 152272 Hom.: 8 Cov.: 33 AF XY: 0.00402 AC XY: 299 AN XY: 74452

African (AFR) AF: 0.0137 AC: 570 AN: 41550

American (AMR) AF: 0.00425 AC: 65 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68026

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.00139 Hom.: 3

Bravo AF: 0.00534

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00999 AC: 44

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00137 AC: 166

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Laron-type isolated somatotropin defect (2)
-	-	2	not provided (2)
1	-	-	Short stature due to partial GHR deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	12
DANN	Benign	0.41
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	-1.0	N
PhyloP100		1.3
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.23
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.24
MVP		0.77
MPC		0.041
ClinPred		0.0012	T
GERP RS		2.0
Varity_R		0.059
gMVP		0.29
Mutation Taster		=91/9	polymorphism

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: rs6413484; hg19: chr5-42699970;