rs121918118

Positions:

chr7-30971183-T-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000823.4(GHRHR):c.431T>A(p.Leu144His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000545 in 1,523,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

GHRHR
NM_000823.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 7.58

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:

GHRHR (HGNC:):

GHRHR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.965

PP5

Variant 7-30971183-T-A is Pathogenic according to our data. Variant chr7-30971183-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 15991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-30971183-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GHRHR	NM_000823.4 linkuse as main transcript	c.431T>A	p.Leu144His	missense_variant	5/13	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.431T>A	p.Leu144His	missense_variant	5/13	1	NM_000823.4	ENSP00000320180.2		Q02643

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000240

AC:

AN:

166580

Hom.:

AF XY:

0.0000114

AC XY:

AN XY:

87608

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000775

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000302

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000569

AC:

AN:

1370986

Hom.:

Cov.:

AF XY:

0.0000604

AC XY:

AN XY:

678866

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000273

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000705

Gnomad4 OTH exome

AF:

0.0000525

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152300

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000473

Bravo

AF:

0.0000113

ExAC

AF:

0.00000880

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Isolated growth hormone deficiency, type 4

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 28, 2023	Variant summary: GHRHR c.431T>A (p.Leu144His) results in a non-conservative amino acid change located in the GPCR, family 2-like, 7TM domain (IPR017981) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 166580 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.431T>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Isolated growth hormone deficiency, type 4 (e.g., Salvatori_2001, Correa_2017, Cohen_2019). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function, finding that the variant resulted in the failure to show a cAMP response, likely due to disrupted ligand binding (e.g., Salvatori_2001, Alba_2005). The following publications have been ascertained in the context of this evaluation (PMID: 15196883, 31231873, 29412390, 11232012). One submitter has reported clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 09, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GHRHR function (PMID: 11232012, 31231873). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GHRHR protein function. ClinVar contains an entry for this variant (Variation ID: 15991). This missense change has been observed in individuals with growth hormone deficiency (PMID: 11232012, 31231873). It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 144 of the GHRHR protein (p.Leu144His). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.65

D;.

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.71

T;T

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Uncertain

-0.14

MutationAssessor

Pathogenic

3.6

H;.

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-6.8

D;D

REVEL

Uncertain

0.62

Sift

Uncertain

0.013

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.94

MVP

0.93

MPC

0.55

ClinPred

0.99

GERP RS

5.3

Varity_R

0.93

gMVP

0.90

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