Genetic Variant GRK3:c.747+124A>G (chr22-25679039-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005160.4(GRK3):c.747+124A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0386 in 589,346 control chromosomes in the GnomAD database, including 3,774 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as (no stars).

Frequency

Genomes: 𝑓 0.11 ( 2911 hom., cov: 33)

Exomes 𝑓: 0.014 ( 863 hom. )

Consequence

GRK3
NM_005160.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.558

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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.368 is higher than 0.05.

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.747+124A>G		intron	N/A	NP_005151.2	P35626
	GRK3	NM_001362778.2		c.408+124A>G		intron	N/A	NP_001349707.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GRK3	ENST00000324198.11	TSL:1 MANE Select	c.747+124A>G	intron	N/A	ENSP00000317578.4	P35626
GRK3	ENST00000869559.1		c.747+124A>G	intron	N/A	ENSP00000539618.1
GRK3	ENST00000947204.1		c.645+124A>G	intron	N/A	ENSP00000617263.1

Frequencies

GnomAD3 genomes

AF:

0.109

AC:

16604

AN:

152058

Hom.:

2903

Cov.:

show subpopulations

Gnomad AFR

AF:

0.373

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0522

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00602

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.00204

Gnomad OTH

AF:

0.0809

GnomAD4 exome

AF:

0.0139

AC:

6078

AN:

437172

Hom.:

863

AF XY:

0.0119

AC XY:

2748

AN XY:

230640

show subpopulations

African (AFR)

AF:

0.377

AC:

4009

AN:

10640

American (AMR)

AF:

0.0333

AC:

458

AN:

13772

Ashkenazi Jewish (ASJ)

AF:

0.0118

AC:

143

AN:

12138

East Asian (EAS)

AF:

0.000149

AC:

AN:

26800

South Asian (SAS)

AF:

0.00443

AC:

158

AN:

35674

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40260

Middle Eastern (MID)

AF:

0.0288

AC:

AN:

3302

European-Non Finnish (NFE)

AF:

0.00138

AC:

372

AN:

270538

Other (OTH)

AF:

0.0349

AC:

839

AN:

24048

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

208

417

625

834

1042

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

174

232

290

<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:

0.109

AC:

16649

AN:

152174

Hom.:

2911

Cov.:

AF XY:

0.106

AC XY:

7872

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.373

AC:

15461

AN:

41494

American (AMR)

AF:

0.0520

AC:

795

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5182

South Asian (SAS)

AF:

0.00581

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00204

AC:

139

AN:

68000

Other (OTH)

AF:

0.0805

AC:

170

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

557

1115

1672

2230

2787

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

142

284

426

568

710

<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:

0.0963

Hom.:

281

Bravo

AF:

0.125

Asia WGS

AF:

0.0280

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.85

(source)

DANN

Benign

0.51

PhyloP100

-0.56

Mutation Taster

=100/0

polymorphism (auto)

(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

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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