Genetic Variant NM_182982.3:c.765A>C (chr4-3019664-A-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_182982.3(GRK4):c.765A>C(p.Glu255Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,613,598 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 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

GRK4
NM_182982.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.920

Publications

1 publications found

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]

GRK4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20143199).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182982.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GRK4	NM_182982.3	MANE Select	c.765A>C	p.Glu255Asp	missense	Exon 9 of 16	NP_892027.2	P32298-1
GRK4	NM_001004056.2		c.669A>C	p.Glu223Asp	missense	Exon 8 of 15	NP_001004056.1	P32298-2
GRK4	NM_001004057.2		c.765A>C	p.Glu255Asp	missense	Exon 9 of 15	NP_001004057.1	P32298-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GRK4	ENST00000398052.9	TSL:1 MANE Select	c.765A>C	p.Glu255Asp	missense	Exon 9 of 16	ENSP00000381129.4	P32298-1
GRK4	ENST00000345167.10	TSL:1	c.669A>C	p.Glu223Asp	missense	Exon 8 of 15	ENSP00000264764.8	P32298-2
GRK4	ENST00000504933.1	TSL:1	c.765A>C	p.Glu255Asp	missense	Exon 9 of 15	ENSP00000427445.1	P32298-4

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000837

AC:

AN:

250906

AF XY:

0.0000959

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000441

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000111

AC:

162

AN:

1461308

Hom.:

Cov.:

AF XY:

0.000117

AC XY:

AN XY:

726900

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33454

American (AMR)

AF:

0.000134

AC:

AN:

44630

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.000453

AC:

AN:

86182

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000998

AC:

111

AN:

1111690

Other (OTH)

AF:

0.0000497

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

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:

0.0000394

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41566

American (AMR)

AF:

0.0000654

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.0000795

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000494

AC:

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

Uncertain

0.45

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.019

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.4

PhyloP100

0.92

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.38

Sift

Benign

0.072

Sift4G

Benign

0.11

Polyphen

0.66

Vest4

0.56

MutPred

0.73

Loss of methylation at K257 (P = 0.07)

MVP

0.67

MPC

0.18

ClinPred

0.28

GERP RS

-1.4

Varity_R

0.74

gMVP

0.58

Mutation Taster

=21/79

disease causing

(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