rs6179

Variant names:

• chr5-42699942-A-G
• rs6179
• NM_000163.5:c.558A>G

Your query was ambiguous. Multiple possible variants found:

• chr5-42699942-A-G
• chr5-42699942-A-C
• chr5-42699942-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000163.5(GHR):​c.558A>G​(p.Gly186Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.713 in 1,596,728 control chromosomes in the GnomAD database, including 410,555 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.65 (33294 hom., cov: 32)
  • Exomes 𝑓: 0.72 (377261 hom.)
• Consequence: GHR NM_000163.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.163
• Publications: 33 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 5-42699942-A-G is Benign according to our data. Variant chr5-42699942-A-G is described in ClinVar as Benign. ClinVar VariationId is 198051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.163 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.821 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHR	NM_000163.5	MANE Select	c.558A>G	p.Gly186Gly	synonymous	Exon 6 of 10	NP_000154.1	P10912-1
	GHR	NM_001242399.2		c.579A>G	p.Gly193Gly	synonymous	Exon 6 of 10	NP_001229328.1	A0A087X0H5
	GHR	NM_001242400.2		c.558A>G	p.Gly186Gly	synonymous	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.558A>G	p.Gly186Gly	synonymous	Exon 6 of 10	ENSP00000230882.4	P10912-1
	GHR	ENST00000620156.4	TSL:5	c.579A>G	p.Gly193Gly	synonymous	Exon 6 of 10	ENSP00000483403.1	A0A087X0H5
	GHR	ENST00000537449.5	TSL:5	c.558A>G	p.Gly186Gly	synonymous	Exon 6 of 10	ENSP00000442206.2	P10912-1

Frequencies

GnomAD3 genomes AF: 0.648 AC: 98504 AN: 151936 Hom.: 33283 Cov.: 32

Gnomad AFR AF: 0.443

Gnomad AMI AF: 0.597

Gnomad AMR AF: 0.738

Gnomad ASJ AF: 0.702

Gnomad EAS AF: 0.841

Gnomad SAS AF: 0.685

Gnomad FIN AF: 0.697

Gnomad MID AF: 0.684

Gnomad NFE AF: 0.726

Gnomad OTH AF: 0.644

GnomAD2 exomes AF: 0.717 AC: 179881 AN: 250752 AF XY: 0.715

Gnomad AFR exome AF: 0.435

Gnomad AMR exome AF: 0.809

Gnomad ASJ exome AF: 0.694

Gnomad EAS exome AF: 0.848

Gnomad FIN exome AF: 0.694

Gnomad NFE exome AF: 0.727

Gnomad OTH exome AF: 0.707

GnomAD4 exome AF: 0.720 AC: 1039709 AN: 1444674 Hom.: 377261 Cov.: 29 AF XY: 0.719 AC XY: 517201 AN XY: 719804

African (AFR) AF: 0.431 AC: 14308 AN: 33202

American (AMR) AF: 0.799 AC: 35629 AN: 44588

Ashkenazi Jewish (ASJ) AF: 0.697 AC: 18134 AN: 26018

East Asian (EAS) AF: 0.878 AC: 34776 AN: 39590

South Asian (SAS) AF: 0.678 AC: 58233 AN: 85926

European-Finnish (FIN) AF: 0.697 AC: 37232 AN: 53396

Middle Eastern (MID) AF: 0.649 AC: 3729 AN: 5742

European-Non Finnish (NFE) AF: 0.726 AC: 795840 AN: 1096384

Other (OTH) AF: 0.699 AC: 41828 AN: 59828

GnomAD4 genome AF: 0.648 AC: 98533 AN: 152054 Hom.: 33294 Cov.: 32 AF XY: 0.652 AC XY: 48468 AN XY: 74320

African (AFR) AF: 0.442 AC: 18337 AN: 41454

American (AMR) AF: 0.738 AC: 11277 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.702 AC: 2434 AN: 3468

East Asian (EAS) AF: 0.842 AC: 4356 AN: 5174

South Asian (SAS) AF: 0.686 AC: 3309 AN: 4822

European-Finnish (FIN) AF: 0.697 AC: 7360 AN: 10560

Middle Eastern (MID) AF: 0.680 AC: 200 AN: 294

European-Non Finnish (NFE) AF: 0.726 AC: 49354 AN: 67982

Other (OTH) AF: 0.647 AC: 1363 AN: 2106

Alfa AF: 0.696 Hom.: 30420

Bravo AF: 0.642

Asia WGS AF: 0.758 AC: 2637 AN: 3478

EpiCase AF: 0.726

EpiControl AF: 0.719

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Laron-type isolated somatotropin defect (3)
-	-	3	not provided (3)
-	-	1	Short stature due to partial GHR deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	6.2
DANN	Benign	0.71
PhyloP100		0.16
Mutation Taster		=294/6	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: rs6179; hg19: chr5-42700044; COSMIC: COSV50113035;