rs4988496

Positions:

chr7-30969071-G-A

Variant summary

Our verdict is Benign. Variant got -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. 15/20 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 Likely benign.

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

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=0.0044107735).

BP6

Variant 7-30969071-G-A is Benign according to our data. Variant chr7-30969071-G-A is described in ClinVar as [Benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GHRHR	NM_000823.4 linkuse as main transcript	c.169G>A	p.Ala57Thr	missense_variant	3/13	ENST00000326139.7	NP_000814.2	Q02643A0A090N8Y6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GHRHR	ENST00000326139.7 linkuse as main transcript	c.169G>A	p.Ala57Thr	missense_variant	3/13	1	NM_000823.4	ENSP00000320180.2		Q02643

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

GnomAD3 exomes

AF:

0.0649

AC:

12633

AN:

194776

Hom.:

781

AF XY:

0.0599

AC XY:

6220

AN XY:

103760

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 SAS exome

AF:

0.0341

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

Gnomad4 AFR exome

AF:

0.284

Gnomad4 AMR exome

AF:

0.0442

Gnomad4 ASJ exome

AF:

0.0945

Gnomad4 EAS exome

AF:

0.0487

Gnomad4 SAS exome

AF:

0.0356

Gnomad4 FIN exome

AF:

0.0177

Gnomad4 NFE exome

AF:

0.0559

Gnomad4 OTH exome

AF:

0.0729

GnomAD4 genome

AF:

0.115

AC:

17444

AN:

152150

Hom.:

1800

Cov.:

AF XY:

0.110

AC XY:

8215

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.274

Gnomad4 AMR

AF:

0.0664

Gnomad4 ASJ

AF:

0.0926

Gnomad4 EAS

AF:

0.0638

Gnomad4 SAS

AF:

0.0322

Gnomad4 FIN

AF:

0.0160

Gnomad4 NFE

AF:

0.0551

Gnomad4 OTH

AF:

0.100

Alfa

AF:

0.0673

Hom.:

1095

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

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	This variant is associated with the following publications: (PMID: 28910730, 22449891, 10944436, 11502843) -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 01, 2015

- -

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

Mar 06, 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

0.069

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.21

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

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

Varity_R

0.11

gMVP

0.37

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