5-42711179-A-G

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.619-28A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.027 in 1,586,480 control chromosomes in the GnomAD database, including 831 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.042 ( 187 hom., cov: 32)

Exomes 𝑓: 0.025 ( 644 hom. )

Consequence

GHR
NM_000163.5 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.751

Publications

3 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

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 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=-0.84).

BP6

Variant 5-42711179-A-G is Benign according to our data. Variant chr5-42711179-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.081 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHR	NM_000163.5 link	c.619-28A>G		intron_variant	Intron 6 of 9	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.619-28A>G		intron_variant	Intron 6 of 9	1	NM_000163.5	ENSP00000230882.4		P10912-1

Frequencies

GnomAD3 genomes

AF:

0.0422

AC:

6426

AN:

152150

Hom.:

187

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0834

Gnomad AMI

AF:

0.0406

Gnomad AMR

AF:

0.0325

Gnomad ASJ

AF:

0.0397

Gnomad EAS

AF:

0.0190

Gnomad SAS

AF:

0.0246

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:

7050

AN:

251034

AF XY:

0.0281

show subpopulations

Gnomad AFR exome

AF:

0.0836

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:

36328

AN:

1434212

Hom.:

644

Cov.:

AF XY:

0.0256

AC XY:

18304

AN XY:

715258

show subpopulations

African (AFR)

AF:

0.0862

AC:

2826

AN:

32778

American (AMR)

AF:

0.0206

AC:

920

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.0462

AC:

1198

AN:

25930

East Asian (EAS)

AF:

0.0238

AC:

941

AN:

39550

South Asian (SAS)

AF:

0.0288

AC:

2469

AN:

85680

European-Finnish (FIN)

AF:

0.0148

AC:

787

AN:

53268

Middle Eastern (MID)

AF:

0.0650

AC:

371

AN:

5710

European-Non Finnish (NFE)

AF:

0.0231

AC:

25070

AN:

1087130

Other (OTH)

AF:

0.0294

AC:

1746

AN:

59480

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

1600

3200

4800

6400

8000

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

940

1880

2820

3760

4700

<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:

0.0422

AC:

6433

AN:

152268

Hom.:

187

Cov.:

AF XY:

0.0406

AC XY:

3025

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0833

AC:

3463

AN:

41552

American (AMR)

AF:

0.0323

AC:

494

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0397

AC:

138

AN:

3472

East Asian (EAS)

AF:

0.0191

AC:

AN:

5186

South Asian (SAS)

AF:

0.0246

AC:

119

AN:

4830

European-Finnish (FIN)

AF:

0.0142

AC:

151

AN:

10626

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0268

AC:

1824

AN:

68000

Other (OTH)

AF:

0.0426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

318

636

954

1272

1590

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:

0.0375

Hom.:

Bravo

AF:

0.0447

Asia WGS

AF:

0.0200

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 20, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.29

(source)

DANN

Benign

0.65

PhyloP100

0.75

BranchPoint Hunter

1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.20

Position offset: 28

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over