rs121909362

Variant names:

• chr5-42699919-C-T
• rs121909362
• NM_000163.5:c.535C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-42699919-C-T
• chr5-42699919-C-G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM1 BP4_Moderate BP6 BS1 BS2

The NM_000163.5(GHR):​c.535C>T​(p.Arg179Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00458 in 1,595,748 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts 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. R179H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0040 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0046 (19 hom.)
• Consequence: GHR NM_000163.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4 B:5
• Conservation: PhyloP100: 1.30
• Publications: 22 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 -9 ACMG points.

• PM1: In a hotspot region, there are 4 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=0.085534275).
• BP6: Variant 5-42699919-C-T is Benign according to our data. Variant chr5-42699919-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 8637.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00402 (612/152228) while in subpopulation AMR AF = 0.00759 (116/15290). AF 95% confidence interval is 0.00647. There are 3 homozygotes in GnomAd4. There are 307 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.535C>T	p.Arg179Cys	missense	Exon 6 of 10	NP_000154.1	P10912-1
	GHR	NM_001242399.2		c.556C>T	p.Arg186Cys	missense	Exon 6 of 10	NP_001229328.1	A0A087X0H5
	GHR	NM_001242400.2		c.535C>T	p.Arg179Cys	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.535C>T	p.Arg179Cys	missense	Exon 6 of 10	ENSP00000230882.4	P10912-1
	GHR	ENST00000620156.4	TSL:5	c.556C>T	p.Arg186Cys	missense	Exon 6 of 10	ENSP00000483403.1	A0A087X0H5
	GHR	ENST00000537449.5	TSL:5	c.535C>T	p.Arg179Cys	missense	Exon 6 of 10	ENSP00000442206.2	P10912-1

Frequencies

GnomAD3 genomes AF: 0.00402 AC: 612 AN: 152110 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000966

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00760

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00227

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00597

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00391 AC: 980 AN: 250850 AF XY: 0.00396

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00273

Gnomad ASJ exome AF: 0.00239

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00287

Gnomad NFE exome AF: 0.00584

Gnomad OTH exome AF: 0.00458

GnomAD4 exome AF: 0.00464 AC: 6702 AN: 1443520 Hom.: 19 Cov.: 25 AF XY: 0.00462 AC XY: 3323 AN XY: 719324

African (AFR) AF: 0.00111 AC: 37 AN: 33238

American (AMR) AF: 0.00305 AC: 136 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.00177 AC: 46 AN: 25996

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39576

South Asian (SAS) AF: 0.00301 AC: 259 AN: 85916

European-Finnish (FIN) AF: 0.00337 AC: 180 AN: 53408

Middle Eastern (MID) AF: 0.00244 AC: 14 AN: 5746

European-Non Finnish (NFE) AF: 0.00529 AC: 5789 AN: 1095286

Other (OTH) AF: 0.00402 AC: 240 AN: 59738

GnomAD4 genome AF: 0.00402 AC: 612 AN: 152228 Hom.: 3 Cov.: 33 AF XY: 0.00413 AC XY: 307 AN XY: 74420

African (AFR) AF: 0.000963 AC: 40 AN: 41540

American (AMR) AF: 0.00759 AC: 116 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4820

European-Finnish (FIN) AF: 0.00227 AC: 24 AN: 10588

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00597 AC: 406 AN: 68028

Other (OTH) AF: 0.00332 AC: 7 AN: 2108

Alfa AF: 0.00535 Hom.: 11

Bravo AF: 0.00385

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00814 AC: 70

ExAC AF: 0.00409 AC: 496

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	1	-	GHR-related disorder (1)
-	-	1	Laron-type isolated somatotropin defect (1)
-	1	-	Laron-type isolated somatotropin defect;C0745103:Hypercholesterolemia, familial, 1;C1858656:Short stature due to partial GHR deficiency;C5887324:Short stature due to growth hormone secretagogue receptor deficiency (1)
-	1	-	Laron-type isolated somatotropin defect;C1858656:Short stature due to partial GHR deficiency (1)
-	-	1	not specified (1)
1	-	-	Short stature due to partial GHR deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Uncertain	0.12
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.034
Eigen_PC	Benign	0.012
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.086	T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	1.0	L
PhyloP100		1.3
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.79	N
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.72	P
Vest4		0.65
MVP		0.98
MPC		0.061
ClinPred		0.047	T
GERP RS		3.2
Varity_R		0.71
gMVP		0.68
Mutation Taster		=79/21	polymorphism

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: rs121909362; hg19: chr5-42700021; COSMIC: COSV99039086;