NM_182982.3:c.1457T>A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_182982.3(GRK4):​c.1457T>A​(p.Val486Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GRK4 NM_182982.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.10
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04578355).

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.1457T>A	p.Val486Glu	missense	Exon 14 of 16	NP_892027.2
	GRK4	NM_001004056.2		c.1361T>A	p.Val454Glu	missense	Exon 13 of 15	NP_001004056.1
	GRK4	NM_001004057.2		c.1457T>A	p.Val486Glu	missense	Exon 14 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.1457T>A	p.Val486Glu	missense	Exon 14 of 16	ENSP00000381129.4
	GRK4	ENST00000345167.10	TSL:1	c.1361T>A	p.Val454Glu	missense	Exon 13 of 15	ENSP00000264764.8
	GRK4	ENST00000504933.1	TSL:1	c.1457T>A	p.Val486Glu	missense	Exon 14 of 15	ENSP00000427445.1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458468 Hom.: 0 Cov.: 40 AF XY: 0.00000138 AC XY: 1 AN XY: 725072

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39616

South Asian (SAS) AF: 0.00 AC: 0 AN: 86106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109236

Other (OTH) AF: 0.00 AC: 0 AN: 60192

GnomAD4 genome Cov.: 28

EpiCase AF: 0.000110

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	11
DANN	Benign	0.52
DEOGEN2	Benign	0.17	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.085	N
PhyloP100		2.1
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.090
Sift	Benign	0.25	T
Sift4G	Benign	0.48	T
Polyphen		0.55	P
Vest4		0.24
MutPred		0.42		Loss of methylation at K488 (P = 0.0445)
MVP		0.081
MPC		0.11
ClinPred		0.83	D
GERP RS		-6.2
Varity_R		0.20
gMVP		0.47
Mutation Taster		=96/4	polymorphism

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;