dbSNP rs6183: GHR:p.Pro495Thr (chr5-42718990-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001242399.2(GHR):c.1504C>A(p.Pro502Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000701 in 1,610,444 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P502P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0011 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00066 ( 11 hom. )

Consequence

GHR
NM_001242399.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.94

Publications

22 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008959115).

BP6

Variant 5-42718990-C-A is Benign according to our data. Variant chr5-42718990-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 353685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00112 (170/152254) while in subpopulation EAS AF = 0.0288 (149/5176). AF 95% confidence interval is 0.025. There are 2 homozygotes in GnomAd4. There are 99 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR,Unknown,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001242399.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GHR	NM_000163.5	MANE Select	c.1483C>A	p.Pro495Thr	missense	Exon 10 of 10	NP_000154.1
GHR	NM_001242399.2		c.1504C>A	p.Pro502Thr	missense	Exon 10 of 10	NP_001229328.1
GHR	NM_001242400.2		c.1483C>A	p.Pro495Thr	missense	Exon 11 of 11	NP_001229329.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GHR	ENST00000230882.9	TSL:1 MANE Select	c.1483C>A	p.Pro495Thr	missense	Exon 10 of 10	ENSP00000230882.4
GHR	ENST00000620156.4	TSL:5	c.1504C>A	p.Pro502Thr	missense	Exon 10 of 10	ENSP00000483403.1
GHR	ENST00000537449.5	TSL:5	c.1483C>A	p.Pro495Thr	missense	Exon 10 of 10	ENSP00000442206.2

Frequencies

GnomAD3 genomes

AF:

0.00111

AC:

169

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0289

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00229

AC:

572

AN:

249264

AF XY:

0.00209

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000871

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0295

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00197

GnomAD4 exome

AF:

0.000658

AC:

959

AN:

1458190

Hom.:

Cov.:

AF XY:

0.000625

AC XY:

453

AN XY:

724818

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33386

American (AMR)

AF:

0.0000897

AC:

AN:

44584

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25922

East Asian (EAS)

AF:

0.0200

AC:

792

AN:

39650

South Asian (SAS)

AF:

0.000571

AC:

AN:

85800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53284

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00000721

AC:

AN:

1109558

Other (OTH)

AF:

0.00174

AC:

105

AN:

60254

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

135

202

270

337

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00112

AC:

170

AN:

152254

Hom.:

Cov.:

AF XY:

0.00133

AC XY:

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41550

American (AMR)

AF:

0.000327

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.0288

AC:

149

AN:

5176

South Asian (SAS)

AF:

0.00228

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.000792

Hom.:

Bravo

AF:

0.00122

ExAC

AF:

0.00199

AC:

242

Asia WGS

AF:

0.0160

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

GHR-related disorder (1)

Laron-type isolated somatotropin defect (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.98

MetaRNN

Benign

0.0090

MetaSVM

Uncertain

-0.14

MutationAssessor

Pathogenic

4.0

PhyloP100

3.9

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-6.9

REVEL

Uncertain

0.37

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0030

Polyphen

0.96

Vest4

0.53

MVP

0.91

MPC

0.32

ClinPred

0.19

GERP RS

5.8

Varity_R

0.82

gMVP

0.64

Mutation Taster

=93/7

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over