rs2228078

Positions:

Variant summary

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

The NM_000823.4(GHRHR):c.1265T>C(p.Met422Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0238 in 1,613,800 control chromosomes in the GnomAD database, including 2,066 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 0.029 ( 255 hom., cov: 33)

Exomes 𝑓: 0.023 ( 1811 hom. )

Consequence

GHRHR
NM_000823.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.0660

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=0.00125435).

BP6

Variant 7-30979237-T-C is Benign according to our data. Variant chr7-30979237-T-C is described in ClinVar as [Benign]. Clinvar id is 360037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-30979237-T-C is described in Lovd as [Benign]. Variant chr7-30979237-T-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.149 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.1265T>C	p.Met422Thr	missense_variant	13/13	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.1265T>C	p.Met422Thr	missense_variant	13/13	1	NM_000823.4	ENSP00000320180	P1

Frequencies

GnomAD3 genomes

AF:

0.0289

AC:

4402

AN:

152236

Hom.:

252

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0148

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.153

Gnomad ASJ

AF:

0.0222

Gnomad EAS

AF:

0.00308

Gnomad SAS

AF:

0.0370

Gnomad FIN

AF:

0.0134

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0143

Gnomad OTH

AF:

0.0244

GnomAD3 exomes

AF:

0.0503

AC:

12634

AN:

251138

Hom.:

1351

AF XY:

0.0430

AC XY:

5843

AN XY:

135788

show subpopulations

Gnomad AFR exome

AF:

0.0131

Gnomad AMR exome

AF:

0.257

Gnomad ASJ exome

AF:

0.0185

Gnomad EAS exome

AF:

0.00353

Gnomad SAS exome

AF:

0.0392

Gnomad FIN exome

AF:

0.0112

Gnomad NFE exome

AF:

0.0141

Gnomad OTH exome

AF:

0.0391

GnomAD4 exome

AF:

0.0232

AC:

33972

AN:

1461446

Hom.:

1811

Cov.:

AF XY:

0.0231

AC XY:

16767

AN XY:

727034

show subpopulations

Gnomad4 AFR exome

AF:

0.0117

Gnomad4 AMR exome

AF:

0.243

Gnomad4 ASJ exome

AF:

0.0190

Gnomad4 EAS exome

AF:

0.00262

Gnomad4 SAS exome

AF:

0.0397

Gnomad4 FIN exome

AF:

0.0115

Gnomad4 NFE exome

AF:

0.0149

Gnomad4 OTH exome

AF:

0.0231

GnomAD4 genome

AF:

0.0289

AC:

4407

AN:

152354

Hom.:

255

Cov.:

AF XY:

0.0310

AC XY:

2313

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.0147

Gnomad4 AMR

AF:

0.154

Gnomad4 ASJ

AF:

0.0222

Gnomad4 EAS

AF:

0.00309

Gnomad4 SAS

AF:

0.0364

Gnomad4 FIN

AF:

0.0134

Gnomad4 NFE

AF:

0.0142

Gnomad4 OTH

AF:

0.0241

Alfa

AF:

0.0155

Hom.:

Bravo

AF:

0.0396

ESP6500AA

AF:

0.0138

AC:

ESP6500EA

AF:

0.0145

AC:

125

ExAC

AF:

0.0410

AC:

4972

Asia WGS

AF:

0.0220

AC:

AN:

3478

EpiCase

AF:

0.0145

EpiControl

AF:

0.0153

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 22449891) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 28, 2018

- -

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

0.064

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.72

DEOGEN2

Benign

0.12

T;.

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.070

LIST_S2

Benign

0.42

T;T

MetaRNN

Benign

0.0013

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

L;.

MutationTaster

Benign

0.99

D;D;D;N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

0.41

N;N

REVEL

Benign

0.077

Sift

Benign

0.20

T;T

Sift4G

Benign

0.074

T;T

Polyphen

0.026

B;B

Vest4

0.038

MPC

0.11

ClinPred

0.00082

GERP RS

-0.058

Varity_R

0.055

gMVP

0.51

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