rs4988498

Positions:

chr7-30969961-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000823.4(GHRHR):c.363G>T(p.Glu121Asp) variant causes a missense 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. 14/20 in silico tools predict 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
NM_000823.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.00900

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 36274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-30969961-G-T is described in Lovd as [Benign].

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GHRHR	NM_000823.4 linkuse as main transcript	c.363G>T	p.Glu121Asp	missense_variant	4/13	ENST00000326139.7	NP_000814.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GHRHR	ENST00000326139.7 linkuse as main transcript	c.363G>T	p.Glu121Asp	missense_variant	4/13	1	NM_000823.4	ENSP00000320180	P1

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

GnomAD3 exomes

AF:

0.0455

AC:

11440

AN:

251486

Hom.:

425

AF XY:

0.0440

AC XY:

5977

AN XY:

135922

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 SAS exome

AF:

0.0321

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

Gnomad4 AFR exome

AF:

0.143

Gnomad4 AMR exome

AF:

0.0282

Gnomad4 ASJ exome

AF:

0.0660

Gnomad4 EAS exome

AF:

0.000132

Gnomad4 SAS exome

AF:

0.0339

Gnomad4 FIN exome

AF:

0.0176

Gnomad4 NFE exome

AF:

0.0562

Gnomad4 OTH exome

AF:

0.0545

GnomAD4 genome

AF:

0.0691

AC:

10527

AN:

152270

Hom.:

521

Cov.:

AF XY:

0.0657

AC XY:

4892

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.133

Gnomad4 AMR

AF:

0.0434

Gnomad4 ASJ

AF:

0.0639

Gnomad4 EAS

AF:

0.000966

Gnomad4 SAS

AF:

0.0276

Gnomad4 FIN

AF:

0.0160

Gnomad4 NFE

AF:

0.0529

Gnomad4 OTH

AF:

0.0663

Alfa

AF:

0.0545

Hom.:

668

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

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

GHRHR-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Idiopathic growth hormone deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 18, 2011

- -

Isolated growth hormone deficiency type IB

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.11

T;.

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.50

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.53

T;T

MetaRNN

Benign

0.0023

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.86

L;.

MutationTaster

Benign

0.68

P;P;P;P;P

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.030

N;N

REVEL

Benign

0.032

Sift

Benign

0.66

T;T

Sift4G

Benign

0.44

T;T

Polyphen

0.0010

B;B

Vest4

0.15

MutPred

0.11

Gain of loop (P = 0.0851);.;

MPC

0.083

ClinPred

0.0059

GERP RS

2.3

Varity_R

0.070

gMVP

0.36

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over