dbSNP rs749248762: GRK4:p.Pro138Thr (chr4-3004303-C-A) – 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_182982.3(GRK4):c.412C>A(p.Pro138Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P138S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

GRK4
NM_182982.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.11

Publications

0 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: 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=0.37539253).

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.412C>A	p.Pro138Thr	missense	Exon 5 of 16	NP_892027.2	P32298-1
GRK4	NM_001004056.2		c.316C>A	p.Pro106Thr	missense	Exon 4 of 15	NP_001004056.1	P32298-2
GRK4	NM_001004057.2		c.412C>A	p.Pro138Thr	missense	Exon 5 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.412C>A	p.Pro138Thr	missense	Exon 5 of 16	ENSP00000381129.4	P32298-1
GRK4	ENST00000345167.10	TSL:1	c.316C>A	p.Pro106Thr	missense	Exon 4 of 15	ENSP00000264764.8	P32298-2
GRK4	ENST00000504933.1	TSL:1	c.412C>A	p.Pro138Thr	missense	Exon 5 of 15	ENSP00000427445.1	P32298-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251312

AF XY:

0.00000736

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460804

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726778

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33428

American (AMR)

AF:

0.00

AC:

AN:

44650

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86212

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111196

Other (OTH)

AF:

0.00

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.75

M_CAP

Benign

0.0071

MetaRNN

Benign

0.38

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

PhyloP100

2.1

PrimateAI

Benign

0.30

PROVEAN

Pathogenic

-5.2

REVEL

Benign

0.15

Sift

Benign

0.16

Sift4G

Benign

0.48

Polyphen

0.84

Vest4

0.52

MutPred

0.49

Loss of glycosylation at P138 (P = 0.0224)

MVP

0.63

MPC

0.33

ClinPred

0.97

GERP RS

2.9

Varity_R

0.76

gMVP

0.50

Mutation Taster

=73/27

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over