Variant 4-2988819-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_182982.3(GRK4):c.241A>G(p.Ile81Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000648 in 1,607,408 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00060 ( 3 hom. )

Consequence

GRK4
NM_182982.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.20

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 made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008204997).

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRK4	NM_182982.3 linkuse as main transcript	c.241A>G	p.Ile81Val	missense_variant	3/16	ENST00000398052.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRK4	ENST00000398052.9 linkuse as main transcript	c.241A>G	p.Ile81Val	missense_variant	3/16	1	NM_182982.3	P1	P32298-1
GRK4	ENST00000345167.10 linkuse as main transcript	c.145A>G	p.Ile49Val	missense_variant	2/15	1			P32298-2
GRK4	ENST00000504933.1 linkuse as main transcript	c.241A>G	p.Ile81Val	missense_variant	3/15	1			P32298-4
GRK4	ENST00000398051.8 linkuse as main transcript	c.145A>G	p.Ile49Val	missense_variant	2/14	1			P32298-3

Frequencies

GnomAD3 genomes

AF:

0.00108

AC:

164

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00125

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00353

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000706

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000827

AC:

208

AN:

251400

Hom.:

AF XY:

0.000802

AC XY:

109

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.00286

Gnomad ASJ exome

AF:

0.000595

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000677

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000600

AC:

873

AN:

1455110

Hom.:

Cov.:

AF XY:

0.000594

AC XY:

430

AN XY:

724366

show subpopulations

Gnomad4 AFR exome

AF:

0.000870

Gnomad4 AMR exome

AF:

0.00277

Gnomad4 ASJ exome

AF:

0.000345

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.000163

Gnomad4 FIN exome

AF:

0.0000563

Gnomad4 NFE exome

AF:

0.000492

Gnomad4 OTH exome

AF:

0.00191

GnomAD4 genome

AF:

0.00110

AC:

168

AN:

152298

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00125

Gnomad4 AMR

AF:

0.00353

Gnomad4 ASJ

AF:

0.000289

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000706

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.000968

Hom.:

Bravo

AF:

0.00133

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000585

AC:

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.000600

EpiControl

AF:

0.000771

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

Jul 19, 2022

The c.241A>G (p.I81V) alteration is located in exon 3 (coding exon 3) of the GRK4 gene. This alteration results from a A to G substitution at nucleotide position 241, causing the isoleucine (I) at amino acid position 81 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.56

DANN

Benign

0.49

DEOGEN2

Benign

0.089

.;T;.;.

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.74

T;T;T;T

M_CAP

Benign

0.0034

MetaRNN

Benign

0.0082

T;T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.4

.;L;.;L

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.62

N;N;N;N

REVEL

Benign

0.076

Sift

Benign

0.57

T;T;T;T

Sift4G

Benign

0.53

T;T;T;T

Polyphen

0.056

B;B;B;B

Vest4

0.12

MVP

0.16

MPC

0.063

ClinPred

0.00083

GERP RS

1.7

Varity_R

0.15

gMVP

0.19

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over