Genetic Variant NM_005160.4:c.113+140C>G (chr22-25565293-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_005160.4(GRK3):c.113+140C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 429,418 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.011 ( 21 hom., cov: 32)

Exomes 𝑓: 0.014 ( 49 hom. )

Consequence

GRK3
NM_005160.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.858

Publications

1 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:

GRK3-AS1 (HGNC:55679): (GRK3 antisense RNA 1)

GRK3-AS1 links:

Genome browser will be placed here

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=-0.75).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0111 (1691/152224) while in subpopulation NFE AF = 0.0175 (1187/67990). AF 95% confidence interval is 0.0166. There are 21 homozygotes in GnomAd4. There are 753 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRK3	NM_005160.4 link	c.113+140C>G		intron_variant	Intron 1 of 20	ENST00000324198.11	NP_005151.2	P35626A0A024R1D8Q8N433

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRK3	ENST00000324198.11 link	c.113+140C>G		intron_variant	Intron 1 of 20	1	NM_005160.4	ENSP00000317578.4		P35626

Frequencies

GnomAD3 genomes

AF:

0.0111

AC:

1693

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00234

Gnomad AMI

AF:

0.00440

Gnomad AMR

AF:

0.0135

Gnomad ASJ

AF:

0.0274

Gnomad EAS

AF:

0.000389

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.00499

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0175

Gnomad OTH

AF:

0.0148

GnomAD4 exome

AF:

0.0140

AC:

3894

AN:

277194

Hom.:

AF XY:

0.0135

AC XY:

2036

AN XY:

150334

show subpopulations

African (AFR)

AF:

0.00373

AC:

AN:

5098

American (AMR)

AF:

0.0117

AC:

AN:

5366

Ashkenazi Jewish (ASJ)

AF:

0.0276

AC:

213

AN:

7722

East Asian (EAS)

AF:

0.00

AC:

AN:

18362

South Asian (SAS)

AF:

0.00582

AC:

150

AN:

25754

European-Finnish (FIN)

AF:

0.00541

AC:

130

AN:

24010

Middle Eastern (MID)

AF:

0.0233

AC:

AN:

1244

European-Non Finnish (NFE)

AF:

0.0177

AC:

3081

AN:

174124

Other (OTH)

AF:

0.0135

AC:

209

AN:

15514

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

175

350

525

700

875

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.0111

AC:

1691

AN:

152224

Hom.:

Cov.:

AF XY:

0.0101

AC XY:

753

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.00233

AC:

AN:

41572

American (AMR)

AF:

0.0135

AC:

207

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0274

AC:

AN:

3472

East Asian (EAS)

AF:

0.000389

AC:

AN:

5136

South Asian (SAS)

AF:

0.00311

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00499

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0175

AC:

1187

AN:

67990

Other (OTH)

AF:

0.0147

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

173

259

346

432

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00430

Hom.:

Bravo

AF:

0.0116

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

3.5

(source)

DANN

Benign

0.55

PhyloP100

-0.86

Mutation Taster

=100/0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over