Genetic Variant GHR:p.Trp34Cys (chr5-42629069-G-C) – ACMG Classification: Likely_benign (-2 pts)

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0770

Publications

2 publications found

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 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)

GHR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

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 link	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 link	c.102G>C	p.Trp34Cys	missense_variant	Exon 3 of 10	1	NM_000163.5	ENSP00000230882.4

Frequencies

GnomAD3 genomes

AF:

0.0000152

AC:

AN:

131430

Hom.:

Cov.:

show subpopulations

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:

AN:

1285996

Hom.:

Cov.:

AF XY:

0.00000777

AC XY:

AN XY:

643478

show subpopulations

African (AFR)

AF:

0.0000798

AC:

AN:

25072

American (AMR)

AF:

0.0000473

AC:

AN:

42324

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23880

East Asian (EAS)

AF:

0.00

AC:

AN:

38468

South Asian (SAS)

AF:

0.00

AC:

AN:

78712

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49794

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4990

European-Non Finnish (NFE)

AF:

0.00000825

AC:

AN:

969534

Other (OTH)

AF:

0.00

AC:

AN:

53222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000152

AC:

AN:

131430

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

64032

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31000

American (AMR)

AF:

0.00

AC:

AN:

13652

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3200

East Asian (EAS)

AF:

0.00

AC:

AN:

4892

South Asian (SAS)

AF:

0.00

AC:

AN:

4182

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9452

Middle Eastern (MID)

AF:

0.00

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.0000321

AC:

AN:

62264

Other (OTH)

AF:

0.00

AC:

AN:

1764

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

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

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

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

LIST_S2

Benign

0.0

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

M_CAP

Benign

0.027

MetaRNN

Benign

0.19

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

MetaSVM

Benign

-0.72

MutationAssessor

Benign

0.0

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

PhyloP100

0.077

PrimateAI

Benign

0.25

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

Vest4

0.48

ClinPred

0.099

GERP RS

2.4

Varity_R

0.11

gMVP

0.57

Mutation Taster

=86/14

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over