Genetic Variant GRK3:p.Thr54Ser (chr22-25604424-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_005160.4(GRK3):c.161C>G(p.Thr54Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,611,572 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 (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

GRK3
NM_005160.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.89

Publications

0 publications found

Variant links:

Genes affected

GRK3 (HGNC:290): (G protein-coupled receptor kinase 3) The beta-adrenergic receptor kinase specifically phosphorylates the agonist-occupied form of the beta-adrenergic and related G protein-coupled receptors. Overall, the beta adrenergic receptor kinase 2 has 85% amino acid similarity with beta adrenergic receptor kinase 1, with the protein kinase catalytic domain having 95% similarity. These data suggest the existence of a family of receptor kinases which may serve broadly to regulate receptor function. [provided by RefSeq, Jul 2008]

GRK3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.39400792).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005160.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRK3	NM_005160.4	MANE Select	c.161C>G	p.Thr54Ser	missense	Exon 2 of 21	NP_005151.2	P35626
	GRK3	NM_001362778.2		c.-105C>G		5_prime_UTR	Exon 2 of 20	NP_001349707.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GRK3	ENST00000324198.11	TSL:1 MANE Select	c.161C>G	p.Thr54Ser	missense	Exon 2 of 21	ENSP00000317578.4	P35626
GRK3	ENST00000869559.1		c.161C>G	p.Thr54Ser	missense	Exon 3 of 22	ENSP00000539618.1
GRK3	ENST00000947204.1		c.161C>G	p.Thr54Ser	missense	Exon 2 of 20	ENSP00000617263.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152174

Hom.:

Cov.:

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000802

AC:

AN:

249352

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1459398

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726024

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33356

American (AMR)

AF:

0.00

AC:

AN:

44136

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26052

East Asian (EAS)

AF:

0.00

AC:

AN:

39632

South Asian (SAS)

AF:

0.00

AC:

AN:

85808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53290

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111072

Other (OTH)

AF:

0.00

AC:

AN:

60296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.48

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

Eigen

Benign

-0.036

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.0051

MetaRNN

Benign

0.39

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.4

PhyloP100

6.9

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.85

REVEL

Benign

0.15

Sift

Benign

0.46

Sift4G

Benign

0.76

Polyphen

0.053

Vest4

0.67

MutPred

0.48

Loss of ubiquitination at K57 (P = 0.1016)

MVP

0.043

MPC

0.49

ClinPred

0.62

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

gMVP

0.33

Mutation Taster

=72/28

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over