chr7-30964121-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000823.4(GHRHR):​c.53C>T​(p.Pro18Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000209 in 1,548,698 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P18P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

GHRHR
NM_000823.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.263
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 Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.050522536).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GHRHRNM_000823.4 linkuse as main transcriptc.53C>T p.Pro18Leu missense_variant 1/13 ENST00000326139.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GHRHRENST00000326139.7 linkuse as main transcriptc.53C>T p.Pro18Leu missense_variant 1/131 NM_000823.4 P1
GHRHRENST00000466427.1 linkuse as main transcriptn.285-4713C>T intron_variant, non_coding_transcript_variant 5

Frequencies

GnomAD3 genomes
AF:
0.000237
AC:
36
AN:
152184
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000523
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:
0.000323
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000182
AC:
28
AN:
153766
Hom.:
0
AF XY:
0.000173
AC XY:
14
AN XY:
81130
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000202
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:
0.000365
Gnomad OTH exome
AF:
0.000227
GnomAD4 exome
AF:
0.000203
AC:
284
AN:
1396396
Hom.:
0
Cov.:
32
AF XY:
0.000202
AC XY:
139
AN XY:
688834
show subpopulations
Gnomad4 AFR exome
AF:
0.0000317
Gnomad4 AMR exome
AF:
0.000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000379
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000243
Gnomad4 OTH exome
AF:
0.000173
GnomAD4 genome
AF:
0.000263
AC:
40
AN:
152302
Hom.:
0
Cov.:
33
AF XY:
0.000215
AC XY:
16
AN XY:
74478
show subpopulations
Gnomad4 AFR
AF:
0.000120
Gnomad4 AMR
AF:
0.000784
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000323
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000259
Hom.:
0
Bravo
AF:
0.000340
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000407
AC:
3
ExAC
AF:
0.0000848
AC:
4

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 20, 2021This sequence change replaces proline with leucine at codon 18 of the GHRHR protein (p.Pro18Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs202243828, ExAC 0.05%). This missense change has been observed in individual(s) with isolated growth hormone deficiency (PMID: 18785993). This variant is also known as c.101C>T. ClinVar contains an entry for this variant (Variation ID: 1031665). 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. 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. -
Isolated growth hormone deficiency type IB Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsApr 11, 2018This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.083
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.48
CADD
Benign
11
DANN
Benign
0.77
DEOGEN2
Benign
0.18
T
Eigen
Benign
-0.98
Eigen_PC
Benign
-0.99
FATHMM_MKL
Benign
0.052
N
LIST_S2
Benign
0.72
T
M_CAP
Benign
0.010
T
MetaRNN
Benign
0.051
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.6
L
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-1.2
N
REVEL
Benign
0.065
Sift
Benign
0.32
T
Sift4G
Benign
0.81
T
Polyphen
0.0090
B
Vest4
0.26
MVP
0.50
MPC
0.092
ClinPred
0.026
T
GERP RS
2.7
Varity_R
0.027
gMVP
0.29

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.

Other links and lift over

dbSNP: rs202243828; hg19: chr7-31003736; API