4-3004316-C-T

Variant names:

• chr4-3004316-C-T
• rs1024323
• NM_182982.3:c.425C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_182982.3(GRK4):​c.425C>T​(p.Ala142Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 1,605,814 control chromosomes in the GnomAD database, including 118,246 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.43 (15464 hom., cov: 31)
  • Exomes 𝑓: 0.37 (102782 hom.)
• Consequence: GRK4 NM_182982.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.544
• Publications: 135 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.150716E-5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.593 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRK4	NM_182982.3	MANE Select	c.425C>T	p.Ala142Val	missense	Exon 5 of 16	NP_892027.2
	GRK4	NM_001004056.2		c.329C>T	p.Ala110Val	missense	Exon 4 of 15	NP_001004056.1
	GRK4	NM_001004057.2		c.425C>T	p.Ala142Val	missense	Exon 5 of 15	NP_001004057.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRK4	ENST00000398052.9	TSL:1 MANE Select	c.425C>T	p.Ala142Val	missense	Exon 5 of 16	ENSP00000381129.4
	GRK4	ENST00000345167.10	TSL:1	c.329C>T	p.Ala110Val	missense	Exon 4 of 15	ENSP00000264764.8
	GRK4	ENST00000504933.1	TSL:1	c.425C>T	p.Ala142Val	missense	Exon 5 of 15	ENSP00000427445.1

Frequencies

GnomAD3 genomes AF: 0.434 AC: 65828 AN: 151838 Hom.: 15425 Cov.: 31

Gnomad AFR AF: 0.599

Gnomad AMI AF: 0.372

Gnomad AMR AF: 0.342

Gnomad ASJ AF: 0.373

Gnomad EAS AF: 0.178

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.533

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.380

Gnomad OTH AF: 0.396

GnomAD2 exomes AF: 0.364 AC: 91329 AN: 251050 AF XY: 0.353

Gnomad AFR exome AF: 0.596

Gnomad AMR exome AF: 0.358

Gnomad ASJ exome AF: 0.376

Gnomad EAS exome AF: 0.180

Gnomad FIN exome AF: 0.524

Gnomad NFE exome AF: 0.377

Gnomad OTH exome AF: 0.365

GnomAD4 exome AF: 0.368 AC: 534533 AN: 1453858 Hom.: 102782 Cov.: 29 AF XY: 0.362 AC XY: 262220 AN XY: 723706

African (AFR) AF: 0.602 AC: 20040 AN: 33310

American (AMR) AF: 0.357 AC: 15911 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.379 AC: 9884 AN: 26050

East Asian (EAS) AF: 0.174 AC: 6886 AN: 39646

South Asian (SAS) AF: 0.195 AC: 16784 AN: 86096

European-Finnish (FIN) AF: 0.512 AC: 27309 AN: 53336

Middle Eastern (MID) AF: 0.346 AC: 1990 AN: 5752

European-Non Finnish (NFE) AF: 0.375 AC: 413994 AN: 1104916

Other (OTH) AF: 0.361 AC: 21735 AN: 60140

GnomAD4 genome AF: 0.434 AC: 65921 AN: 151956 Hom.: 15464 Cov.: 31 AF XY: 0.434 AC XY: 32231 AN XY: 74268

African (AFR) AF: 0.599 AC: 24825 AN: 41428

American (AMR) AF: 0.342 AC: 5222 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.373 AC: 1292 AN: 3468

East Asian (EAS) AF: 0.177 AC: 916 AN: 5182

South Asian (SAS) AF: 0.199 AC: 958 AN: 4812

European-Finnish (FIN) AF: 0.533 AC: 5623 AN: 10546

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.380 AC: 25803 AN: 67950

Other (OTH) AF: 0.394 AC: 830 AN: 2108

Alfa AF: 0.387 Hom.: 56106

Bravo AF: 0.429

TwinsUK AF: 0.362 AC: 1343

ALSPAC AF: 0.366 AC: 1412

ESP6500AA AF: 0.597 AC: 2631

ESP6500EA AF: 0.381 AC: 3275

ExAC AF: 0.365 AC: 44283

Asia WGS AF: 0.264 AC: 920 AN: 3478

EpiCase AF: 0.368

EpiControl AF: 0.365

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.8
DANN	Benign	0.95
DEOGEN2	Benign	0.062	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.00036	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.000022	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.2	N
PhyloP100		0.54
PrimateAI	Benign	0.32	T
PROVEAN	Benign	1.9	N
REVEL	Benign	0.028
Sift	Benign	0.28	T
Sift4G	Benign	0.39	T
Polyphen		0.0010	B
Vest4		0.058
MPC		0.061
ClinPred		0.0042	T
GERP RS		2.1
Varity_R		0.096
gMVP		0.23
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1024323; hg19: chr4-3006043; COSMIC: COSV61667919;