rs6182

chr5-42718826-G-Cchr5-42718826-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000163.5(GHR):c.1319G>C(p.Cys440Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C440F) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GHR NM_000163.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0140

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.015106797).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GHR	NM_000163.5	c.1319G>C	p.Cys440Ser	missense_variant	10/10	ENST00000230882.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GHR	ENST00000230882.9	c.1319G>C	p.Cys440Ser	missense_variant	10/10	1	NM_000163.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	0.90
Dann	Benign	0.68
DEOGEN2	Benign	0.22	T;T;.;T;T;T;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.026	N
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.015	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-2.6	N;N;.;N;N;N;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	2.1	N;.;.;.;.;.;.;N
REVEL	Benign	0.098
Sift	Benign	1.0	T;.;.;.;.;.;.;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T
Polyphen		0.0	B;B;.;B;B;B;B;.
Vest4		0.049
MutPred		0.34		Gain of glycosylation at C440 (P = 0.0349);Gain of glycosylation at C440 (P = 0.0349);.;Gain of glycosylation at C440 (P = 0.0349);Gain of glycosylation at C440 (P = 0.0349);Gain of glycosylation at C440 (P = 0.0349);Gain of glycosylation at C440 (P = 0.0349);.;
MVP		0.19
MPC		0.054
ClinPred		0.082	T
GERP RS		1.7
Varity_R		0.032
gMVP		0.087

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: rs6182; hg19: chr5-42718928;