rs4988496

Variant names:

Variant summary

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

The NM_000823.4(GHRHR):c.169G>A(p.Ala57Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.065 in 1,578,878 control chromosomes in the GnomAD database, including 5,415 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A57V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.11 ( 1800 hom., cov: 32)

Exomes 𝑓: 0.060 ( 3615 hom. )

Consequence

GHRHR
NM_000823.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.0820

Publications

33 publications found

Variant links:

Genes affected

GHRHR (HGNC:4266): (growth hormone releasing hormone receptor) This gene encodes a receptor for growth hormone-releasing hormone. Binding of this hormone to the receptor leads to synthesis and release of growth hormone. Mutations in this gene have been associated with isolated growth hormone deficiency (IGHD), also known as Dwarfism of Sindh, a disorder characterized by short stature. [provided by RefSeq, Jun 2010]

GHRHR Gene-Disease associations (from GenCC):

isolated growth hormone deficiency type IB
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Laboratory for Molecular Medicine
isolated growth hormone deficiency, type 4
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

GHRHR 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=0.0044107735).

BP6

Variant 7-30969071-G-A is Benign according to our data. Variant chr7-30969071-G-A is described in ClinVar as Benign. ClinVar VariationId is 36273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000823.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHRHR	NM_000823.4	MANE Select	c.169G>A	p.Ala57Thr	missense	Exon 3 of 13	NP_000814.2	A0A090N8Y6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHRHR	ENST00000326139.7	TSL:1 MANE Select	c.169G>A	p.Ala57Thr	missense	Exon 3 of 13	ENSP00000320180.2	Q02643
	GHRHR	ENST00000466427.1	TSL:5	n.*192G>A		downstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.115

AC:

17421

AN:

152030

Hom.:

1795

Cov.:

show subpopulations

Gnomad AFR

AF:

0.275

Gnomad AMI

AF:

0.0877

Gnomad AMR

AF:

0.0665

Gnomad ASJ

AF:

0.0926

Gnomad EAS

AF:

0.0637

Gnomad SAS

AF:

0.0321

Gnomad FIN

AF:

0.0160

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.0551

Gnomad OTH

AF:

0.101

GnomAD2 exomes

AF:

0.0649

AC:

12633

AN:

194776

AF XY:

0.0599

show subpopulations

Gnomad AFR exome

AF:

0.289

Gnomad AMR exome

AF:

0.0413

Gnomad ASJ exome

AF:

0.0892

Gnomad EAS exome

AF:

0.0695

Gnomad FIN exome

AF:

0.0176

Gnomad NFE exome

AF:

0.0557

Gnomad OTH exome

AF:

0.0604

GnomAD4 exome

AF:

0.0597

AC:

85206

AN:

1426728

Hom.:

3615

Cov.:

AF XY:

0.0583

AC XY:

41157

AN XY:

706398

show subpopulations

African (AFR)

AF:

0.284

AC:

9370

AN:

33008

American (AMR)

AF:

0.0442

AC:

1715

AN:

38808

Ashkenazi Jewish (ASJ)

AF:

0.0945

AC:

2399

AN:

25392

East Asian (EAS)

AF:

0.0487

AC:

1874

AN:

38456

South Asian (SAS)

AF:

0.0356

AC:

2906

AN:

81612

European-Finnish (FIN)

AF:

0.0177

AC:

899

AN:

50910

Middle Eastern (MID)

AF:

0.0972

AC:

556

AN:

5722

European-Non Finnish (NFE)

AF:

0.0559

AC:

61176

AN:

1093704

Other (OTH)

AF:

0.0729

AC:

4311

AN:

59116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

4001

8001

12002

16002

20003

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2476

4952

7428

9904

12380

<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:

0.115

AC:

17444

AN:

152150

Hom.:

1800

Cov.:

AF XY:

0.110

AC XY:

8215

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.274

AC:

11384

AN:

41472

American (AMR)

AF:

0.0664

AC:

1016

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0926

AC:

321

AN:

3468

East Asian (EAS)

AF:

0.0638

AC:

328

AN:

5140

South Asian (SAS)

AF:

0.0322

AC:

155

AN:

4818

European-Finnish (FIN)

AF:

0.0160

AC:

170

AN:

10620

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0551

AC:

3744

AN:

68008

Other (OTH)

AF:

0.100

AC:

212

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

690

1380

2069

2759

3449

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

178

356

534

712

890

<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:

0.0755

Hom.:

2147

Bravo

AF:

0.128

TwinsUK

AF:

0.0572

AC:

212

ALSPAC

AF:

0.0586

AC:

226

ESP6500AA

AF:

0.274

AC:

1204

ESP6500EA

AF:

0.0573

AC:

492

ExAC

AF:

0.0577

AC:

6947

Asia WGS

AF:

0.0580

AC:

206

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

GHRHR-related disorder (1)

Idiopathic growth hormone deficiency (1)

Isolated growth hormone deficiency type IB (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.21

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.097

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0040

LIST_S2

Benign

0.011

MetaRNN

Benign

0.0044

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.36

PhyloP100

-0.082

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.26

REVEL

Benign

0.031

Sift

Benign

0.12

Sift4G

Benign

0.67

Polyphen

0.0

Vest4

0.016

MPC

0.087

ClinPred

0.0024

GERP RS

-7.8

PromoterAI

-0.0032

Neutral

(source)

Varity_R

0.11

gMVP

0.37

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over