rs6178

Variant names:

• chr5-42711178-C-T
• rs6178
• NM_000163.5:c.619-29C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000163.5(GHR):​c.619-29C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0269 in 1,581,668 control chromosomes in the GnomAD database, including 829 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.042 (186 hom., cov: 33)
  • Exomes 𝑓: 0.025 (643 hom.)
• Consequence: GHR NM_000163.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0820
• Publications: 4 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 -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 5-42711178-C-T is Benign according to our data. Variant chr5-42711178-C-T is described in ClinVar as Benign. ClinVar VariationId is 255406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0811 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.619-29C>T		intron	N/A	NP_000154.1
	GHR	NM_001242399.2		c.640-29C>T		intron	N/A	NP_001229328.1
	GHR	NM_001242400.2		c.619-29C>T		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.619-29C>T		intron	N/A	ENSP00000230882.4
	GHR	ENST00000620156.4	TSL:5	c.640-29C>T		intron	N/A	ENSP00000483403.1
	GHR	ENST00000537449.5	TSL:5	c.619-29C>T		intron	N/A	ENSP00000442206.2

Frequencies

GnomAD3 genomes AF: 0.0423 AC: 6424 AN: 152010 Hom.: 186 Cov.: 33

Gnomad AFR AF: 0.0835

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.0325

Gnomad ASJ AF: 0.0397

Gnomad EAS AF: 0.0191

Gnomad SAS AF: 0.0247

Gnomad FIN AF: 0.0142

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0268

Gnomad OTH AF: 0.0430

GnomAD2 exomes AF: 0.0281 AC: 7053 AN: 251004 AF XY: 0.0281

Gnomad AFR exome AF: 0.0837

Gnomad AMR exome AF: 0.0187

Gnomad ASJ exome AF: 0.0447

Gnomad EAS exome AF: 0.0182

Gnomad FIN exome AF: 0.0148

Gnomad NFE exome AF: 0.0252

Gnomad OTH exome AF: 0.0306

GnomAD4 exome AF: 0.0253 AC: 36194 AN: 1429540 Hom.: 643 Cov.: 27 AF XY: 0.0256 AC XY: 18239 AN XY: 713208

African (AFR) AF: 0.0863 AC: 2823 AN: 32700

American (AMR) AF: 0.0206 AC: 920 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.0462 AC: 1196 AN: 25896

East Asian (EAS) AF: 0.0238 AC: 941 AN: 39540

South Asian (SAS) AF: 0.0288 AC: 2467 AN: 85540

European-Finnish (FIN) AF: 0.0148 AC: 787 AN: 53232

Middle Eastern (MID) AF: 0.0651 AC: 371 AN: 5700

European-Non Finnish (NFE) AF: 0.0230 AC: 24953 AN: 1082950

Other (OTH) AF: 0.0293 AC: 1736 AN: 59302

GnomAD4 genome AF: 0.0423 AC: 6431 AN: 152128 Hom.: 186 Cov.: 33 AF XY: 0.0407 AC XY: 3023 AN XY: 74364

African (AFR) AF: 0.0834 AC: 3463 AN: 41506

American (AMR) AF: 0.0323 AC: 493 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0397 AC: 138 AN: 3472

East Asian (EAS) AF: 0.0191 AC: 99 AN: 5184

South Asian (SAS) AF: 0.0247 AC: 119 AN: 4820

European-Finnish (FIN) AF: 0.0142 AC: 150 AN: 10574

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0268 AC: 1824 AN: 67980

Other (OTH) AF: 0.0425 AC: 90 AN: 2116

Alfa AF: 0.0294 Hom.: 118

Bravo AF: 0.0447

Asia WGS AF: 0.0200 AC: 69 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	11
DANN	Benign	0.63
PhyloP100		0.082
BranchPoint Hunter		3.0
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: rs6178; hg19: chr5-42711280;