dbSNP rs1172065861: GRK4:p.Tyr167His (chr4-3007791-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_182982.3(GRK4):c.499T>C(p.Tyr167His) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,459,958 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

GRK4
NM_182982.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.10

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRK4	NM_182982.3 link	c.499T>C	p.Tyr167His	missense_variant	Exon 6 of 16	ENST00000398052.9	NP_892027.2	P32298-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GRK4	ENST00000398052.9 link	c.499T>C	p.Tyr167His	missense_variant	Exon 6 of 16	1	NM_182982.3	ENSP00000381129.4	P32298-1
GRK4	ENST00000345167.10 link	c.403T>C	p.Tyr135His	missense_variant	Exon 5 of 15	1		ENSP00000264764.8	P32298-2
GRK4	ENST00000504933.1 link	c.499T>C	p.Tyr167His	missense_variant	Exon 6 of 15	1		ENSP00000427445.1	P32298-4
GRK4	ENST00000398051.8 link	c.403T>C	p.Tyr135His	missense_variant	Exon 5 of 14	1		ENSP00000381128.4	P32298-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

250102

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135190

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1459958

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726290

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.499T>C (p.Y167H) alteration is located in exon 6 (coding exon 6) of the GRK4 gene. This alteration results from a T to C substitution at nucleotide position 499, causing the tyrosine (Y) at amino acid position 167 to be replaced by a histidine (H). 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

0.11

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

.;T;.;.

Eigen

Benign

0.18

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.81

T;T;T;T

M_CAP

Benign

0.0051

MetaRNN

Uncertain

0.45

T;T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Pathogenic

2.9

.;M;.;M

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-4.3

D;D;D;D

REVEL

Benign

0.19

Sift

Benign

0.052

T;D;D;D

Sift4G

Benign

0.16

T;T;T;T

Polyphen

0.70

P;P;B;P

Vest4

0.47

MutPred

0.58

.;Gain of disorder (P = 0.0452);.;Gain of disorder (P = 0.0452);

MVP

0.73

MPC

0.28

ClinPred

0.98

GERP RS

4.4

Varity_R

0.69

gMVP

0.74

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

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