rs4988498

Variant names:

Variant summary

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

The ENST00000409316.5(GHRHR):c.-185G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0539 in 1,190,478 control chromosomes in the GnomAD database, including 2,189 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.069 ( 521 hom., cov: 32)

Exomes 𝑓: 0.052 ( 1668 hom. )

Consequence

GHRHR
ENST00000409316.5 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.00900

Publications

22 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=0.0023173988).

BP6

Variant 7-30969961-G-T is Benign according to our data. Variant chr7-30969961-G-T is described in ClinVar as Benign. ClinVar VariationId is 36274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.13 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000409316.5. 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.363G>T	p.Glu121Asp	missense	Exon 4 of 13	NP_000814.2	A0A090N8Y6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GHRHR	ENST00000409316.5	TSL:1	c.-185G>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 10	ENSP00000386602.1	Q9HB43
GHRHR	ENST00000326139.7	TSL:1 MANE Select	c.363G>T	p.Glu121Asp	missense	Exon 4 of 13	ENSP00000320180.2	Q02643
GHRHR	ENST00000409904.7	TSL:1	c.171G>T	p.Glu57Asp	missense	Exon 1 of 10	ENSP00000387113.3	Q9HB45

Frequencies

GnomAD3 genomes

AF:

0.0691

AC:

10517

AN:

152152

Hom.:

522

Cov.:

show subpopulations

Gnomad AFR

AF:

0.133

Gnomad AMI

AF:

0.0658

Gnomad AMR

AF:

0.0435

Gnomad ASJ

AF:

0.0639

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.0275

Gnomad FIN

AF:

0.0160

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.0530

Gnomad OTH

AF:

0.0670

GnomAD2 exomes

AF:

0.0455

AC:

11440

AN:

251486

AF XY:

0.0440

show subpopulations

Gnomad AFR exome

AF:

0.143

Gnomad AMR exome

AF:

0.0259

Gnomad ASJ exome

AF:

0.0613

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.0174

Gnomad NFE exome

AF:

0.0525

Gnomad OTH exome

AF:

0.0440

GnomAD4 exome

AF:

0.0517

AC:

53695

AN:

1038208

Hom.:

1668

Cov.:

AF XY:

0.0506

AC XY:

27080

AN XY:

535624

show subpopulations

African (AFR)

AF:

0.143

AC:

3646

AN:

25584

American (AMR)

AF:

0.0282

AC:

1249

AN:

44224

Ashkenazi Jewish (ASJ)

AF:

0.0660

AC:

1553

AN:

23546

East Asian (EAS)

AF:

0.000132

AC:

AN:

37788

South Asian (SAS)

AF:

0.0339

AC:

2644

AN:

77988

European-Finnish (FIN)

AF:

0.0176

AC:

938

AN:

53254

Middle Eastern (MID)

AF:

0.0785

AC:

391

AN:

4980

European-Non Finnish (NFE)

AF:

0.0562

AC:

40732

AN:

724286

Other (OTH)

AF:

0.0545

AC:

2537

AN:

46558

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

2746

5492

8238

10984

13730

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1288

2576

3864

5152

6440

<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:

0.0691

AC:

10527

AN:

152270

Hom.:

521

Cov.:

AF XY:

0.0657

AC XY:

4892

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.133

AC:

5505

AN:

41534

American (AMR)

AF:

0.0434

AC:

664

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0639

AC:

222

AN:

3472

East Asian (EAS)

AF:

0.000966

AC:

AN:

5178

South Asian (SAS)

AF:

0.0276

AC:

133

AN:

4824

European-Finnish (FIN)

AF:

0.0160

AC:

170

AN:

10622

Middle Eastern (MID)

AF:

0.0884

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0529

AC:

3602

AN:

68028

Other (OTH)

AF:

0.0663

AC:

140

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

508

1016

1524

2032

2540

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

228

342

456

570

<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:

0.0579

Hom.:

1021

Bravo

AF:

0.0748

TwinsUK

AF:

0.0558

AC:

207

ALSPAC

AF:

0.0568

AC:

219

ESP6500AA

AF:

0.141

AC:

622

ESP6500EA

AF:

0.0540

AC:

464

ExAC

AF:

0.0473

AC:

5740

Asia WGS

AF:

0.0270

AC:

AN:

3478

EpiCase

AF:

0.0545

EpiControl

AF:

0.0544

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)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.11

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.50

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.53

MetaRNN

Benign

0.0023

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.86

PhyloP100

0.0090

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.030

REVEL

Benign

0.032

Sift

Benign

0.66

Sift4G

Benign

0.44

Polyphen

0.0010

Vest4

0.15

MutPred

0.11

Gain of loop (P = 0.0851)

MPC

0.083

ClinPred

0.0059

GERP RS

2.3

PromoterAI

0.072

Neutral

(source)

Varity_R

0.070

gMVP

0.36

Mutation Taster

=98/2

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