chr4-3009659-C-G

Variant summary

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

The NM_182982.3(GRK4):ā€‹c.548C>Gā€‹(p.Thr183Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000236 in 1,613,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: š‘“ 0.000039 ( 0 hom., cov: 32)
Exomes š‘“: 0.000022 ( 0 hom. )

Consequence

GRK4
NM_182982.3 missense

Scores

4
8
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.87
Variant links:
Genes affected
GRK4 (HGNC:4543): (G protein-coupled receptor kinase 4) This gene encodes a member of the guanine nucleotide-binding protein (G protein)-coupled receptor kinase subfamily of the Ser/Thr protein kinase family. The protein phosphorylates the activated forms of G protein-coupled receptors thus initiating its deactivation. This gene has been linked to both genetic and acquired hypertension. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2013]

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=0.12835649).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GRK4NM_182982.3 linkuse as main transcriptc.548C>G p.Thr183Arg missense_variant 7/16 ENST00000398052.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GRK4ENST00000398052.9 linkuse as main transcriptc.548C>G p.Thr183Arg missense_variant 7/161 NM_182982.3 P1P32298-1
GRK4ENST00000345167.10 linkuse as main transcriptc.452C>G p.Thr151Arg missense_variant 6/151 P32298-2
GRK4ENST00000504933.1 linkuse as main transcriptc.548C>G p.Thr183Arg missense_variant 7/151 P32298-4
GRK4ENST00000398051.8 linkuse as main transcriptc.452C>G p.Thr151Arg missense_variant 6/141 P32298-3

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152100
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00116
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000107
AC:
27
AN:
251376
Hom.:
0
AF XY:
0.0000883
AC XY:
12
AN XY:
135872
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00136
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.0000219
AC:
32
AN:
1461180
Hom.:
0
Cov.:
29
AF XY:
0.0000165
AC XY:
12
AN XY:
726916
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000731
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152216
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74426
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00116
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000378
ExAC
AF:
0.0000576
AC:
7

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 29, 2023The c.548C>G (p.T183R) alteration is located in exon 7 (coding exon 7) of the GRK4 gene. This alteration results from a C to G substitution at nucleotide position 548, causing the threonine (T) at amino acid position 183 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Benign
-0.034
T
BayesDel_noAF
Pathogenic
0.14
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.51
.;D;.;.
Eigen
Uncertain
0.61
Eigen_PC
Uncertain
0.63
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Pathogenic
0.98
D;D;D;D
M_CAP
Benign
0.020
T
MetaRNN
Benign
0.13
T;T;T;T
MetaSVM
Benign
-0.29
T
MutationAssessor
Pathogenic
3.0
.;M;.;M
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Benign
0.48
T
PROVEAN
Pathogenic
-5.7
D;D;D;D
REVEL
Uncertain
0.38
Sift
Uncertain
0.0080
D;D;D;D
Sift4G
Uncertain
0.030
D;D;D;D
Polyphen
1.0
D;D;D;D
Vest4
0.56
MutPred
0.15
.;Gain of MoRF binding (P = 0.0638);.;Gain of MoRF binding (P = 0.0638);
MVP
0.83
MPC
0.38
ClinPred
0.41
T
GERP RS
5.8
Varity_R
0.84
gMVP
0.69

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: rs45538934; hg19: chr4-3011386; API