chr4-3004316-C-T

Position:

• chr4-3004316-C-T

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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 Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRK4	NM_182982.3	c.425C>T	p.Ala142Val	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>T	p.Ala142Val	missense_variant	5/16	1	NM_182982.3	ENSP00000381129	P1
GRK4	ENST00000345167.10	c.329C>T	p.Ala110Val	missense_variant	4/15	1		ENSP00000264764
GRK4	ENST00000504933.1	c.425C>T	p.Ala142Val	missense_variant	5/15	1		ENSP00000427445
GRK4	ENST00000398051.8	c.329C>T	p.Ala110Val	missense_variant	4/14	1		ENSP00000381128

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

GnomAD3 exomes AF: 0.364 AC: 91329 AN: 251050 Hom.: 18223 AF XY: 0.353 AC XY: 47841 AN XY: 135682

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 SAS exome AF: 0.191

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

Gnomad4 AFR exome AF: 0.602

Gnomad4 AMR exome AF: 0.357

Gnomad4 ASJ exome AF: 0.379

Gnomad4 EAS exome AF: 0.174

Gnomad4 SAS exome AF: 0.195

Gnomad4 FIN exome AF: 0.512

Gnomad4 NFE exome AF: 0.375

Gnomad4 OTH exome AF: 0.361

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

Gnomad4 AFR AF: 0.599

Gnomad4 AMR AF: 0.342

Gnomad4 ASJ AF: 0.373

Gnomad4 EAS AF: 0.177

Gnomad4 SAS AF: 0.199

Gnomad4 FIN AF: 0.533

Gnomad4 NFE AF: 0.380

Gnomad4 OTH AF: 0.394

Alfa AF: 0.377 Hom.: 26841

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 v4.3

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;T;T;T
MetaRNN	Benign	0.000022	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.2	.;N;.;N
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	1.9	N;N;N;N
REVEL	Benign	0.028
Sift	Benign	0.28	T;T;T;T
Sift4G	Benign	0.39	T;T;T;T
Polyphen		0.0010	B;B;B;B
Vest4		0.058
MPC		0.061
ClinPred		0.0042	T
GERP RS		2.1
Varity_R		0.096
gMVP		0.23

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

Publications

LitVar

Other links and lift over

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