chr4-3037423-T-C

Variant names:

• chr4-3037423-T-C
• rs1801058
• NM_182982.3:c.1457T>C

Variant summary

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

The NM_182982.3(GRK4):​c.1457T>C​(p.Val486Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.603 in 1,609,182 control chromosomes in the GnomAD database, including 297,701 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V486E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.67 (35148 hom., cov: 28)
  • Exomes 𝑓: 0.60 (262553 hom.)
• Consequence: GRK4 NM_182982.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.10
• Publications: 111 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]

ENSG00000296061 (HGNC:58716):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=6.047129E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.848 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRK4	NM_182982.3	MANE Select	c.1457T>C	p.Val486Ala	missense	Exon 14 of 16	NP_892027.2
	GRK4	NM_001004056.2		c.1361T>C	p.Val454Ala	missense	Exon 13 of 15	NP_001004056.1
	GRK4	NM_001004057.2		c.1457T>C	p.Val486Ala	missense	Exon 14 of 15	NP_001004057.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRK4	ENST00000398052.9	TSL:1 MANE Select	c.1457T>C	p.Val486Ala	missense	Exon 14 of 16	ENSP00000381129.4
	GRK4	ENST00000345167.10	TSL:1	c.1361T>C	p.Val454Ala	missense	Exon 13 of 15	ENSP00000264764.8
	GRK4	ENST00000504933.1	TSL:1	c.1457T>C	p.Val486Ala	missense	Exon 14 of 15	ENSP00000427445.1

Frequencies

GnomAD3 genomes AF: 0.668 AC: 101229 AN: 151548 Hom.: 35090 Cov.: 28

Gnomad AFR AF: 0.855

Gnomad AMI AF: 0.595

Gnomad AMR AF: 0.668

Gnomad ASJ AF: 0.642

Gnomad EAS AF: 0.505

Gnomad SAS AF: 0.736

Gnomad FIN AF: 0.496

Gnomad MID AF: 0.662

Gnomad NFE AF: 0.590

Gnomad OTH AF: 0.678

GnomAD2 exomes AF: 0.621 AC: 156019 AN: 251374 AF XY: 0.622

Gnomad AFR exome AF: 0.859

Gnomad AMR exome AF: 0.644

Gnomad ASJ exome AF: 0.637

Gnomad EAS exome AF: 0.498

Gnomad FIN exome AF: 0.505

Gnomad NFE exome AF: 0.588

Gnomad OTH exome AF: 0.613

GnomAD4 exome AF: 0.597 AC: 869520 AN: 1457516 Hom.: 262553 Cov.: 40 AF XY: 0.601 AC XY: 435115 AN XY: 724536

African (AFR) AF: 0.868 AC: 29007 AN: 33428

American (AMR) AF: 0.648 AC: 28949 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.636 AC: 16578 AN: 26056

East Asian (EAS) AF: 0.514 AC: 20351 AN: 39594

South Asian (SAS) AF: 0.742 AC: 63838 AN: 86046

European-Finnish (FIN) AF: 0.514 AC: 27394 AN: 53340

Middle Eastern (MID) AF: 0.711 AC: 4088 AN: 5750

European-Non Finnish (NFE) AF: 0.579 AC: 642088 AN: 1108494

Other (OTH) AF: 0.619 AC: 37227 AN: 60144

GnomAD4 genome AF: 0.668 AC: 101346 AN: 151666 Hom.: 35148 Cov.: 28 AF XY: 0.666 AC XY: 49317 AN XY: 74072

African (AFR) AF: 0.856 AC: 35433 AN: 41404

American (AMR) AF: 0.668 AC: 10153 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.642 AC: 2224 AN: 3466

East Asian (EAS) AF: 0.506 AC: 2590 AN: 5120

South Asian (SAS) AF: 0.737 AC: 3530 AN: 4788

European-Finnish (FIN) AF: 0.496 AC: 5206 AN: 10504

Middle Eastern (MID) AF: 0.654 AC: 191 AN: 292

European-Non Finnish (NFE) AF: 0.590 AC: 40054 AN: 67872

Other (OTH) AF: 0.675 AC: 1425 AN: 2112

Alfa AF: 0.611 Hom.: 129772

Bravo AF: 0.682

TwinsUK AF: 0.583 AC: 2162

ALSPAC AF: 0.573 AC: 2209

ESP6500AA AF: 0.846 AC: 3727

ESP6500EA AF: 0.588 AC: 5057

ExAC AF: 0.626 AC: 76057

Asia WGS AF: 0.598 AC: 2079 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	3.2
DANN	Benign	0.40
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	6.0e-7	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.1
PrimateAI	Benign	0.19	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.078
Sift	Benign	0.060	T
Sift4G	Benign	0.19	T
Polyphen		0.0010	B
Vest4		0.070
MPC		0.072
ClinPred		0.018	T
GERP RS		-6.2
Varity_R		0.052
gMVP		0.30
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1801058; hg19: chr4-3039150; COSMIC: COSV61669219;