4-3037423-T-C

Position:

• chr4-3037423-T-C

Variant summary

Our verdict is Benign. Variant got -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. 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 0.67 (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

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=6.047129E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.848 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRK4	NM_182982.3	c.1457T>C	p.Val486Ala	missense_variant	14/16	ENST00000398052.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRK4	ENST00000398052.9	c.1457T>C	p.Val486Ala	missense_variant	14/16	1	NM_182982.3	P1

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

GnomAD3 exomes AF: 0.621 AC: 156019 AN: 251374 Hom.: 49592 AF XY: 0.622 AC XY: 84559 AN XY: 135844

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 SAS exome AF: 0.741

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

Gnomad4 AFR exome AF: 0.868

Gnomad4 AMR exome AF: 0.648

Gnomad4 ASJ exome AF: 0.636

Gnomad4 EAS exome AF: 0.514

Gnomad4 SAS exome AF: 0.742

Gnomad4 FIN exome AF: 0.514

Gnomad4 NFE exome AF: 0.579

Gnomad4 OTH exome AF: 0.619

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

Gnomad4 AFR AF: 0.856

Gnomad4 AMR AF: 0.668

Gnomad4 ASJ AF: 0.642

Gnomad4 EAS AF: 0.506

Gnomad4 SAS AF: 0.737

Gnomad4 FIN AF: 0.496

Gnomad4 NFE AF: 0.590

Gnomad4 OTH AF: 0.675

Alfa AF: 0.599 Hom.: 59984

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 v4.3

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;T;T;T
MetaRNN	Benign	6.0e-7	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	.;N;.;N
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.19	T
PROVEAN	Benign	0.060	N;N;N;N
REVEL	Benign	0.078
Sift	Benign	0.060	T;T;T;T
Sift4G	Benign	0.19	T;T;T;T
Polyphen		0.0010	B;B;B;B
Vest4		0.070
MPC		0.072
ClinPred		0.018	T
GERP RS		-6.2
Varity_R		0.052
gMVP		0.30

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