chr4-3019675-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_182982.3(GRK4):ā€‹c.776C>Gā€‹(p.Ala259Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

GRK4
NM_182982.3 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.89
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.29160702).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GRK4NM_182982.3 linkuse as main transcriptc.776C>G p.Ala259Gly missense_variant 9/16 ENST00000398052.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GRK4ENST00000398052.9 linkuse as main transcriptc.776C>G p.Ala259Gly missense_variant 9/161 NM_182982.3 P1P32298-1
GRK4ENST00000345167.10 linkuse as main transcriptc.680C>G p.Ala227Gly missense_variant 8/151 P32298-2
GRK4ENST00000504933.1 linkuse as main transcriptc.776C>G p.Ala259Gly missense_variant 9/151 P32298-4
GRK4ENST00000398051.8 linkuse as main transcriptc.680C>G p.Ala227Gly missense_variant 8/141 P32298-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461582
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
727072
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

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 GeneticsDec 08, 2023The c.776C>G (p.A259G) alteration is located in exon 9 (coding exon 9) of the GRK4 gene. This alteration results from a C to G substitution at nucleotide position 776, causing the alanine (A) at amino acid position 259 to be replaced by a glycine (G). 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
0.16
BayesDel_addAF
Benign
-0.091
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.29
.;T;.;.
Eigen
Benign
-0.050
Eigen_PC
Benign
0.063
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.96
D;D;D;D
M_CAP
Benign
0.010
T
MetaRNN
Benign
0.29
T;T;T;T
MetaSVM
Benign
-0.76
T
MutationAssessor
Benign
0.55
.;N;.;N
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Benign
0.24
T
PROVEAN
Uncertain
-3.4
D;D;D;D
REVEL
Benign
0.13
Sift
Benign
0.30
T;T;T;T
Sift4G
Benign
0.34
T;T;T;T
Polyphen
0.64
P;P;B;B
Vest4
0.43
MutPred
0.50
.;Gain of catalytic residue at L260 (P = 0.0871);.;Gain of catalytic residue at L260 (P = 0.0871);
MVP
0.72
MPC
0.19
ClinPred
0.98
D
GERP RS
4.5
Varity_R
0.80
gMVP
0.48

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: rs1261047806; hg19: chr4-3021402; API