Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000163.5(GHR):c.1473C>T(p.Ser491Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0236 in 1,611,654 control chromosomes in the GnomAD database, including 564 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 42 hom., cov: 32)

Exomes 𝑓: 0.024 ( 522 hom. )

Consequence

GHR
NM_000163.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.214

Publications

7 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 5-42718980-C-T is Benign according to our data. Variant chr5-42718980-C-T is described in ClinVar as Benign. ClinVar VariationId is 255404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.214 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0583 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000163.5. 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.1473C>T	p.Ser491Ser	synonymous	Exon 10 of 10	NP_000154.1
GHR	NM_001242399.2		c.1494C>T	p.Ser498Ser	synonymous	Exon 10 of 10	NP_001229328.1
GHR	NM_001242400.2		c.1473C>T	p.Ser491Ser	synonymous	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.1473C>T	p.Ser491Ser	synonymous	Exon 10 of 10	ENSP00000230882.4
GHR	ENST00000620156.4	TSL:5	c.1494C>T	p.Ser498Ser	synonymous	Exon 10 of 10	ENSP00000483403.1
GHR	ENST00000537449.5	TSL:5	c.1473C>T	p.Ser491Ser	synonymous	Exon 10 of 10	ENSP00000442206.2

Frequencies

GnomAD3 genomes

AF:

0.0208

AC:

3161

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00795

Gnomad AMI

AF:

0.0406

Gnomad AMR

AF:

0.0268

Gnomad ASJ

AF:

0.0398

Gnomad EAS

AF:

0.0193

Gnomad SAS

AF:

0.0238

Gnomad FIN

AF:

0.0141

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0266

Gnomad OTH

AF:

0.0273

GnomAD2 exomes

AF:

0.0226

AC:

5657

AN:

250096

AF XY:

0.0240

show subpopulations

Gnomad AFR exome

AF:

0.00695

Gnomad AMR exome

AF:

0.0162

Gnomad ASJ exome

AF:

0.0451

Gnomad EAS exome

AF:

0.0182

Gnomad FIN exome

AF:

0.0147

Gnomad NFE exome

AF:

0.0250

Gnomad OTH exome

AF:

0.0280

GnomAD4 exome

AF:

0.0239

AC:

34875

AN:

1459480

Hom.:

522

Cov.:

AF XY:

0.0243

AC XY:

17651

AN XY:

725700

show subpopulations

African (AFR)

AF:

0.00886

AC:

296

AN:

33416

American (AMR)

AF:

0.0178

AC:

794

AN:

44634

Ashkenazi Jewish (ASJ)

AF:

0.0468

AC:

1216

AN:

26006

East Asian (EAS)

AF:

0.0240

AC:

952

AN:

39662

South Asian (SAS)

AF:

0.0289

AC:

2483

AN:

85998

European-Finnish (FIN)

AF:

0.0148

AC:

787

AN:

53332

Middle Eastern (MID)

AF:

0.0637

AC:

367

AN:

5764

European-Non Finnish (NFE)

AF:

0.0238

AC:

26444

AN:

1110376

Other (OTH)

AF:

0.0255

AC:

1536

AN:

60292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

1966

3932

5897

7863

9829

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

978

1956

2934

3912

4890

<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:

0.0208

AC:

3160

AN:

152174

Hom.:

Cov.:

AF XY:

0.0204

AC XY:

1517

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.00793

AC:

329

AN:

41510

American (AMR)

AF:

0.0267

AC:

408

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0398

AC:

138

AN:

3470

East Asian (EAS)

AF:

0.0193

AC:

100

AN:

5172

South Asian (SAS)

AF:

0.0239

AC:

115

AN:

4818

European-Finnish (FIN)

AF:

0.0141

AC:

149

AN:

10602

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0266

AC:

1809

AN:

67998

Other (OTH)

AF:

0.0270

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

166

332

497

663

829

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0250

Hom.:

Bravo

AF:

0.0208

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0263

EpiControl

AF:

0.0312

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Laron-type isolated somatotropin defect (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

8.2

(source)

DANN

Benign

0.85

PhyloP100

-0.21

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over