Genetic Variant NM_000163.5:c.497G>C (chr5-42699881-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_000163.5(GHR):c.497G>C(p.Gly166Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,456,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

GHR
NM_000163.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.21

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 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

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHR	NM_000163.5 link	c.497G>C	p.Gly166Ala	missense_variant	Exon 6 of 10	ENST00000230882.9	NP_000154.1	P10912-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GHR	ENST00000230882.9 link	c.497G>C	p.Gly166Ala	missense_variant	Exon 6 of 10	1	NM_000163.5	ENSP00000230882.4		P10912-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1456554

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724992

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

9.03e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.70

D;D;.;D;D;D;D;.;.

Eigen

Benign

-0.085

Eigen_PC

Benign

0.0046

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

.;.;D;.;.;D;.;D;D

M_CAP

Benign

0.048

MetaRNN

Benign

0.29

T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.24

MutationAssessor

Benign

1.4

L;L;.;L;L;L;L;.;.

PrimateAI

Benign

0.40

PROVEAN

Benign

-2.3

N;.;.;.;.;.;.;N;.

REVEL

Uncertain

0.42

Sift

Benign

0.095

T;.;.;.;.;.;.;T;.

Sift4G

Benign

0.064

T;T;T;T;T;T;T;T;T

Polyphen

0.085

B;B;.;B;B;B;B;.;.

Vest4

0.26

MutPred

0.65

Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;Gain of sheet (P = 0.0827);

MVP

0.96

MPC

0.23

ClinPred

0.85

GERP RS

3.0

Varity_R

0.31

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.25

Position offset: 12

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over