rs6184

Variant names:

• chr5-42719242-C-A
• rs6184
• NM_000163.5:c.1735C>A

Your query was ambiguous. Multiple possible variants found:

• chr5-42719242-C-A
• chr5-42719242-C-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.1735C>A​(p.Pro579Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0225 in 1,613,872 control chromosomes in the GnomAD database, including 1,925 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (146 hom., cov: 33)
  • Exomes 𝑓: 0.023 (1779 hom.)
• Consequence: GHR NM_000163.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.167
• Publications: 34 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011945367).
• BP6: Variant 5-42719242-C-A is Benign according to our data. Variant chr5-42719242-C-A is described in ClinVar as Benign. ClinVar VariationId is 281096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.165 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.1735C>A	p.Pro579Thr	missense	Exon 10 of 10	NP_000154.1	P10912-1
	GHR	NM_001242399.2		c.1756C>A	p.Pro586Thr	missense	Exon 10 of 10	NP_001229328.1	A0A087X0H5
	GHR	NM_001242400.2		c.1735C>A	p.Pro579Thr	missense	Exon 11 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.1735C>A	p.Pro579Thr	missense	Exon 10 of 10	ENSP00000230882.4	P10912-1
	GHR	ENST00000620156.4	TSL:5	c.1756C>A	p.Pro586Thr	missense	Exon 10 of 10	ENSP00000483403.1	A0A087X0H5
	GHR	ENST00000537449.5	TSL:5	c.1735C>A	p.Pro579Thr	missense	Exon 10 of 10	ENSP00000442206.2	P10912-1

Frequencies

GnomAD3 genomes AF: 0.0179 AC: 2723 AN: 152114 Hom.: 146 Cov.: 33

Gnomad AFR AF: 0.00427

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0169

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.138

Gnomad SAS AF: 0.174

Gnomad FIN AF: 0.00368

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00910

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.0404 AC: 10135 AN: 250926 AF XY: 0.0468

Gnomad AFR exome AF: 0.00400

Gnomad AMR exome AF: 0.0266

Gnomad ASJ exome AF: 0.00993

Gnomad EAS exome AF: 0.133

Gnomad FIN exome AF: 0.00365

Gnomad NFE exome AF: 0.00951

Gnomad OTH exome AF: 0.0252

GnomAD4 exome AF: 0.0230 AC: 33558 AN: 1461642 Hom.: 1779 Cov.: 33 AF XY: 0.0274 AC XY: 19912 AN XY: 727140

African (AFR) AF: 0.00353 AC: 118 AN: 33474

American (AMR) AF: 0.0259 AC: 1157 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00995 AC: 260 AN: 26130

East Asian (EAS) AF: 0.0972 AC: 3858 AN: 39682

South Asian (SAS) AF: 0.169 AC: 14606 AN: 86234

European-Finnish (FIN) AF: 0.00301 AC: 161 AN: 53404

Middle Eastern (MID) AF: 0.0420 AC: 242 AN: 5768

European-Non Finnish (NFE) AF: 0.0102 AC: 11287 AN: 1111860

Other (OTH) AF: 0.0310 AC: 1869 AN: 60384

GnomAD4 genome AF: 0.0179 AC: 2726 AN: 152230 Hom.: 146 Cov.: 33 AF XY: 0.0205 AC XY: 1524 AN XY: 74420

African (AFR) AF: 0.00429 AC: 178 AN: 41534

American (AMR) AF: 0.0174 AC: 266 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 31 AN: 3470

East Asian (EAS) AF: 0.137 AC: 707 AN: 5166

South Asian (SAS) AF: 0.174 AC: 839 AN: 4810

European-Finnish (FIN) AF: 0.00368 AC: 39 AN: 10610

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00910 AC: 619 AN: 68024

Other (OTH) AF: 0.0180 AC: 38 AN: 2112

Alfa AF: 0.0130 Hom.: 137

Bravo AF: 0.0160

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00986 AC: 38

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.00860 AC: 74

ExAC AF: 0.0403 AC: 4892

Asia WGS AF: 0.145 AC: 501 AN: 3478

EpiCase AF: 0.0103

EpiControl AF: 0.0104

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Laron-type isolated somatotropin defect (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.77
DANN	Benign	0.87
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.17
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.034
Sift	Benign	0.065	T
Sift4G	Uncertain	0.046	D
Polyphen		0.0070	B
Vest4		0.024
MPC		0.059
ClinPred		0.0047	T
GERP RS		2.4
Varity_R		0.047
gMVP		0.33
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: rs6184; hg19: chr5-42719344; COSMIC: COSV50115138; COSMIC: COSV50115138;