chr5-42629069-G-C

Variant names:

• chr5-42629069-G-C
• rs121909370
• NM_000163.5:c.102G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000163.5(GHR):​c.102G>C​(p.Trp34Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000988 in 1,417,426 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000015 (0 hom., cov: 21)
  • Exomes 𝑓: 0.0000093 (1 hom.)
• Consequence: GHR NM_000163.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0770
• Publications: 2 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18617094).

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.102G>C	p.Trp34Cys	missense	Exon 3 of 10	NP_000154.1
	GHR	NM_001242399.2		c.123G>C	p.Trp41Cys	missense	Exon 3 of 10	NP_001229328.1
	GHR	NM_001242400.2		c.102G>C	p.Trp34Cys	missense	Exon 4 of 11	NP_001229329.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHR	ENST00000230882.9	TSL:1 MANE Select	c.102G>C	p.Trp34Cys	missense	Exon 3 of 10	ENSP00000230882.4
	GHR	ENST00000620156.4	TSL:5	c.123G>C	p.Trp41Cys	missense	Exon 3 of 10	ENSP00000483403.1
	GHR	ENST00000537449.5	TSL:5	c.102G>C	p.Trp34Cys	missense	Exon 3 of 10	ENSP00000442206.2

Frequencies

GnomAD3 genomes AF: 0.0000152 AC: 2 AN: 131430 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000321

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000933 AC: 12 AN: 1285996 Hom.: 1 Cov.: 26 AF XY: 0.00000777 AC XY: 5 AN XY: 643478

African (AFR) AF: 0.0000798 AC: 2 AN: 25072

American (AMR) AF: 0.0000473 AC: 2 AN: 42324

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23880

East Asian (EAS) AF: 0.00 AC: 0 AN: 38468

South Asian (SAS) AF: 0.00 AC: 0 AN: 78712

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49794

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4990

European-Non Finnish (NFE) AF: 0.00000825 AC: 8 AN: 969534

Other (OTH) AF: 0.00 AC: 0 AN: 53222

GnomAD4 genome AF: 0.0000152 AC: 2 AN: 131430 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 64032

African (AFR) AF: 0.00 AC: 0 AN: 31000

American (AMR) AF: 0.00 AC: 0 AN: 13652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3200

East Asian (EAS) AF: 0.00 AC: 0 AN: 4892

South Asian (SAS) AF: 0.00 AC: 0 AN: 4182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9452

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.0000321 AC: 2 AN: 62264

Other (OTH) AF: 0.00 AC: 0 AN: 1764

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	14
DANN	Benign	0.93
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.077
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.58	N
REVEL	Benign	0.17
Sift	Uncertain	0.014	D
Sift4G	Benign	0.18	T
Polyphen		0.18	B
Vest4		0.48
MutPred		0.43		Gain of catalytic residue at P33 (P = 0.0103)
MVP		0.82
MPC		0.086
ClinPred		0.099	T
GERP RS		2.4
Varity_R		0.11
gMVP		0.57
Mutation Taster		=86/14	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: rs121909370; hg19: chr5-42629171; COSMIC: COSV106084322;