chr4-3022431-A-C
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP3BP4_ModerateBS1_SupportingBS2
The NM_182982.3(GRK4):c.950A>C(p.Asn317Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000851 in 1,613,988 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00080 ( 1 hom., cov: 33)
Exomes 𝑓: 0.00086 ( 10 hom. )
Consequence
GRK4
NM_182982.3 missense
NM_182982.3 missense
Scores
10
4
3
Clinical Significance
Conservation
PhyloP100: 8.68
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 Likely_benign. Variant got -6 ACMG points.
PP3
?
Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
?
Computational evidence support a benign effect (MetaRNN=0.13934132).
BS1
?
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000857 (1252/1461658) while in subpopulation MID AF= 0.0194 (112/5768). AF 95% confidence interval is 0.0165. There are 10 homozygotes in gnomad4_exome. There are 674 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
?
High Homozygotes in GnomAdExome at 2 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GRK4 | NM_182982.3 | c.950A>C | p.Asn317Thr | missense_variant | 10/16 | ENST00000398052.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GRK4 | ENST00000398052.9 | c.950A>C | p.Asn317Thr | missense_variant | 10/16 | 1 | NM_182982.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000802 AC: 122AN: 152212Hom.: 1 Cov.: 33
GnomAD3 genomes
?
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122
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33
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GnomAD3 exomes AF: 0.00117 AC: 295AN: 251126Hom.: 2 AF XY: 0.00127 AC XY: 172AN XY: 135722
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GnomAD4 exome AF: 0.000857 AC: 1252AN: 1461658Hom.: 10 Cov.: 30 AF XY: 0.000927 AC XY: 674AN XY: 727124
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GnomAD4 genome ? AF: 0.000801 AC: 122AN: 152330Hom.: 1 Cov.: 33 AF XY: 0.000779 AC XY: 58AN XY: 74492
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?
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0
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2
ESP6500AA
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0
ESP6500EA
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7
ExAC
?
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120
Asia WGS
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4
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3478
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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 submitter | clinical testing | Ambry Genetics | Sep 16, 2021 | The c.950A>C (p.N317T) alteration is located in exon 10 (coding exon 10) of the GRK4 gene. This alteration results from a A to C substitution at nucleotide position 950, causing the asparagine (N) at amino acid position 317 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
D;D;D;D
Vest4
MVP
MPC
0.39
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at