NM_000823.4:c.1265T>C

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.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. 15/21 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

Publications

13 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: Laboratory for Molecular Medicine, Orphanet
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=0.00125435).

BP6

Variant 7-30979237-T-C is Benign according to our data. Variant chr7-30979237-T-C is described in ClinVar as Benign. ClinVar VariationId is 360037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
GHRHR	NM_000823.4 link	c.1265T>C	p.Met422Thr	missense_variant	Exon 13 of 13	ENST00000326139.7	NP_000814.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GHRHR	ENST00000326139.7 link	c.1265T>C	p.Met422Thr	missense_variant	Exon 13 of 13	1	NM_000823.4	ENSP00000320180.2

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

GnomAD2 exomes

AF:

0.0503

AC:

12634

AN:

251138

AF XY:

0.0430

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 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

African (AFR)

AF:

0.0117

AC:

393

AN:

33476

American (AMR)

AF:

0.243

AC:

10875

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.0190

AC:

496

AN:

26124

East Asian (EAS)

AF:

0.00262

AC:

104

AN:

39680

South Asian (SAS)

AF:

0.0397

AC:

3428

AN:

86242

European-Finnish (FIN)

AF:

0.0115

AC:

615

AN:

53314

Middle Eastern (MID)

AF:

0.0240

AC:

138

AN:

5752

European-Non Finnish (NFE)

AF:

0.0149

AC:

16530

AN:

1111788

Other (OTH)

AF:

0.0231

AC:

1393

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

1822

3645

5467

7290

9112

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

792

1584

2376

3168

3960

<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:

0.0289

AC:

4407

AN:

152354

Hom.:

255

Cov.:

AF XY:

0.0310

AC XY:

2313

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.0147

AC:

612

AN:

41586

American (AMR)

AF:

0.154

AC:

2353

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0222

AC:

AN:

3472

East Asian (EAS)

AF:

0.00309

AC:

AN:

5180

South Asian (SAS)

AF:

0.0364

AC:

176

AN:

4832

European-Finnish (FIN)

AF:

0.0134

AC:

142

AN:

10622

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0142

AC:

969

AN:

68034

Other (OTH)

AF:

0.0241

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

206

412

619

825

1031

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0174

Hom.:

260

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

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22449891) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jun 28, 2018

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Isolated growth hormone deficiency type IB

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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;.

PhyloP100

0.066

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

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over