5-42629069-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 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. 16/21 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a topological_domain Extracellular (size 245) in uniprot entity GHR_HUMAN there are 39 pathogenic changes around while only 4 benign (91%) in NM_000163.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.18617094).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHR	NM_000163.5	c.102G>C	p.Trp34Cys	missense_variant	Exon 3 of 10	ENST00000230882.9	NP_000154.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GHR	ENST00000230882.9	c.102G>C	p.Trp34Cys	missense_variant	Exon 3 of 10	1	NM_000163.5	ENSP00000230882.4

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

Gnomad4 AFR exome AF: 0.0000798

Gnomad4 AMR exome AF: 0.0000473

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000825

Gnomad4 OTH exome AF: 0.00

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000321

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;T;.;T;T;T;T;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.86	.;.;D;.;.;D;.;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.0	N;N;.;N;N;N;N;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.58	N;.;.;.;.;.;.;.
REVEL	Benign	0.17
Sift	Uncertain	0.014	D;.;.;.;.;.;.;.
Sift4G	Benign	0.18	T;T;T;T;T;T;T;T
Polyphen		0.18	B;B;.;B;B;B;B;.
Vest4		0.48
MutPred		0.43		Gain of catalytic residue at P33 (P = 0.0103);Gain of catalytic residue at P33 (P = 0.0103);.;Gain of catalytic residue at P33 (P = 0.0103);Gain of catalytic residue at P33 (P = 0.0103);Gain of catalytic residue at P33 (P = 0.0103);Gain of catalytic residue at P33 (P = 0.0103);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs121909370; hg19: chr5-42629171;