7-30964079-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000823.4(GHRHR):​c.11G>A​(p.Arg4Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000226 in 1,550,576 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

GHRHR
NM_000823.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.514
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.071184754).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GHRHRNM_000823.4 linkuse as main transcriptc.11G>A p.Arg4Gln missense_variant 1/13 ENST00000326139.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GHRHRENST00000326139.7 linkuse as main transcriptc.11G>A p.Arg4Gln missense_variant 1/131 NM_000823.4 P1
GHRHRENST00000466427.1 linkuse as main transcriptn.285-4755G>A intron_variant, non_coding_transcript_variant 5

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152230
Hom.:
0
Cov.:
33
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:
0.00
GnomAD3 exomes
AF:
0.0000773
AC:
12
AN:
155190
Hom.:
0
AF XY:
0.0000612
AC XY:
5
AN XY:
81760
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000364
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000878
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000166
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000229
AC:
32
AN:
1398228
Hom.:
0
Cov.:
32
AF XY:
0.0000232
AC XY:
16
AN XY:
689650
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000280
Gnomad4 ASJ exome
AF:
0.0000397
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000505
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000148
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152348
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74508
show subpopulations
Gnomad4 AFR
AF:
0.0000240
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:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.0000189
ExAC
AF:
0.0000184
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 17, 2022This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 4 of the GHRHR protein (p.Arg4Gln). This variant is present in population databases (rs573168850, gnomAD 0.03%). This missense change has been observed in individual(s) with isolated growth hormone deficiency (PMID: 27501283). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect GHRHR function (PMID: 27501283). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.080
BayesDel_addAF
Benign
-0.42
T
BayesDel_noAF
Benign
-0.53
CADD
Benign
14
DANN
Benign
0.97
DEOGEN2
Benign
0.12
T
Eigen
Benign
-0.63
Eigen_PC
Benign
-0.76
FATHMM_MKL
Benign
0.039
N
LIST_S2
Benign
0.49
T
M_CAP
Benign
0.0098
T
MetaRNN
Benign
0.071
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.9
L
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.24
T
PROVEAN
Benign
-0.26
N
REVEL
Benign
0.067
Sift
Benign
0.47
T
Sift4G
Benign
0.25
T
Polyphen
0.96
D
Vest4
0.13
MutPred
0.31
Loss of MoRF binding (P = 0.0092);
MVP
0.51
MPC
0.12
ClinPred
0.036
T
GERP RS
1.9
Varity_R
0.024
gMVP
0.27

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs573168850; hg19: chr7-31003694; COSMIC: COSV58196549; API