rs1024323

Positions:

• chr4-3004316-C-A
• chr4-3004316-C-G
• chr4-3004316-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_182982.3(GRK4):​c.425C>A​(p.Ala142Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 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. A142V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: GRK4 NM_182982.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.544

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18688372).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRK4	NM_182982.3	c.425C>A	p.Ala142Asp	missense_variant	5/16	ENST00000398052.9	NP_892027.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRK4	ENST00000398052.9	c.425C>A	p.Ala142Asp	missense_variant	5/16	1	NM_182982.3	ENSP00000381129	P1
GRK4	ENST00000345167.10	c.329C>A	p.Ala110Asp	missense_variant	4/15	1		ENSP00000264764
GRK4	ENST00000504933.1	c.425C>A	p.Ala142Asp	missense_variant	5/15	1		ENSP00000427445
GRK4	ENST00000398051.8	c.329C>A	p.Ala110Asp	missense_variant	4/14	1		ENSP00000381128

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	.;T;.;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.21	T;T;T;T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.2	.;L;.;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.7	D;D;D;D
REVEL	Benign	0.073
Sift	Benign	0.10	T;T;T;T
Sift4G	Benign	0.089	T;T;T;T
Polyphen		0.96	D;P;P;D
Vest4		0.12
MutPred		0.57		.;Gain of ubiquitination at K141 (P = 0.0443);.;Gain of ubiquitination at K141 (P = 0.0443);
MVP		0.51
MPC		0.089
ClinPred		0.73	D
GERP RS		2.1
Varity_R		0.49
gMVP		0.57

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

Other links and lift over

dbSNP: rs1024323; hg19: chr4-3006043;