rs6178

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000163.5(GHR):c.619-29C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0269 in 1,581,668 control chromosomes in the GnomAD database, including 829 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.042 ( 186 hom., cov: 33)

Exomes 𝑓: 0.025 ( 643 hom. )

Consequence

GHR
NM_000163.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.0820

Publications

4 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
short stature due to partial GHR deficiency
Inheritance: AD, Unknown Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

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

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 5-42711178-C-T is Benign according to our data. Variant chr5-42711178-C-T is described in ClinVar as Benign. ClinVar VariationId is 255406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0811 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	Effect	Exon Rank	Protein	UniProt
GHR	NM_000163.5	MANE Select	c.619-29C>T	intron	N/A	NP_000154.1	P10912-1
GHR	NM_001242399.2		c.640-29C>T	intron	N/A	NP_001229328.1	A0A087X0H5
GHR	NM_001242400.2		c.619-29C>T	intron	N/A	NP_001229329.1	P10912-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GHR	ENST00000230882.9	TSL:1 MANE Select	c.619-29C>T	intron	N/A	ENSP00000230882.4	P10912-1
GHR	ENST00000620156.4	TSL:5	c.640-29C>T	intron	N/A	ENSP00000483403.1	A0A087X0H5
GHR	ENST00000537449.5	TSL:5	c.619-29C>T	intron	N/A	ENSP00000442206.2	P10912-1

Frequencies

GnomAD3 genomes

AF:

0.0423

AC:

6424

AN:

152010

Hom.:

186

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0835

Gnomad AMI

AF:

0.0406

Gnomad AMR

AF:

0.0325

Gnomad ASJ

AF:

0.0397

Gnomad EAS

AF:

0.0191

Gnomad SAS

AF:

0.0247

Gnomad FIN

AF:

0.0142

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0268

Gnomad OTH

AF:

0.0430

GnomAD2 exomes

AF:

0.0281

AC:

7053

AN:

251004

AF XY:

0.0281

show subpopulations

Gnomad AFR exome

AF:

0.0837

Gnomad AMR exome

AF:

0.0187

Gnomad ASJ exome

AF:

0.0447

Gnomad EAS exome

AF:

0.0182

Gnomad FIN exome

AF:

0.0148

Gnomad NFE exome

AF:

0.0252

Gnomad OTH exome

AF:

0.0306

GnomAD4 exome

AF:

0.0253

AC:

36194

AN:

1429540

Hom.:

643

Cov.:

AF XY:

0.0256

AC XY:

18239

AN XY:

713208

show subpopulations

African (AFR)

AF:

0.0863

AC:

2823

AN:

32700

American (AMR)

AF:

0.0206

AC:

920

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.0462

AC:

1196

AN:

25896

East Asian (EAS)

AF:

0.0238

AC:

941

AN:

39540

South Asian (SAS)

AF:

0.0288

AC:

2467

AN:

85540

European-Finnish (FIN)

AF:

0.0148

AC:

787

AN:

53232

Middle Eastern (MID)

AF:

0.0651

AC:

371

AN:

5700

European-Non Finnish (NFE)

AF:

0.0230

AC:

24953

AN:

1082950

Other (OTH)

AF:

0.0293

AC:

1736

AN:

59302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

1566

3131

4697

6262

7828

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

934

1868

2802

3736

4670

<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:

0.0423

AC:

6431

AN:

152128

Hom.:

186

Cov.:

AF XY:

0.0407

AC XY:

3023

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.0834

AC:

3463

AN:

41506

American (AMR)

AF:

0.0323

AC:

493

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.0397

AC:

138

AN:

3472

East Asian (EAS)

AF:

0.0191

AC:

AN:

5184

South Asian (SAS)

AF:

0.0247

AC:

119

AN:

4820

European-Finnish (FIN)

AF:

0.0142

AC:

150

AN:

10574

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0268

AC:

1824

AN:

67980

Other (OTH)

AF:

0.0425

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

316

632

949

1265

1581

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

234

312

390

<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:

0.0294

Hom.:

118

Bravo

AF:

0.0447

Asia WGS

AF:

0.0200

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

(source)

DANN

Benign

0.63

PhyloP100

0.082

BranchPoint Hunter

3.0

Mutation Taster

=100/0

polymorphism (auto)

(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