chr4-3037423-T-G

Position:

• chr4-3037423-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_182982.3(GRK4):​c.1457T>G​(p.Val486Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. V486A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 28)
• 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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06145692).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRK4	NM_182982.3	c.1457T>G	p.Val486Gly	missense_variant	14/16	ENST00000398052.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRK4	ENST00000398052.9	c.1457T>G	p.Val486Gly	missense_variant	14/16	1	NM_182982.3	P1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 40

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	13
DANN	Benign	0.89
DEOGEN2	Benign	0.22	.;T;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.84	T;T;T;T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.061	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	.;L;.;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-2.0	N;N;N;N
REVEL	Benign	0.11
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.017	D;D;D;D
Polyphen		0.20	B;B;B;B
Vest4		0.19
MutPred		0.41		.;Loss of stability (P = 0.0044);.;Loss of stability (P = 0.0044);
MVP		0.099
MPC		0.086
ClinPred		0.86	D
GERP RS		-6.2
Varity_R		0.31
gMVP		0.39

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;