4-2988819-A-G

Position:

• chr4-2988819-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_182982.3(GRK4):​c.241A>G​(p.Ile81Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000648 in 1,607,408 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (3 hom.)
• Consequence: GRK4 NM_182982.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.20

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008204997).
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRK4	NM_182982.3	c.241A>G	p.Ile81Val	missense_variant	3/16	ENST00000398052.9	NP_892027.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRK4	ENST00000398052.9	c.241A>G	p.Ile81Val	missense_variant	3/16	1	NM_182982.3	ENSP00000381129	P1
GRK4	ENST00000345167.10	c.145A>G	p.Ile49Val	missense_variant	2/15	1		ENSP00000264764
GRK4	ENST00000504933.1	c.241A>G	p.Ile81Val	missense_variant	3/15	1		ENSP00000427445
GRK4	ENST00000398051.8	c.145A>G	p.Ile49Val	missense_variant	2/14	1		ENSP00000381128

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 164 AN: 152180 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000827 AC: 208 AN: 251400 Hom.: 1 AF XY: 0.000802 AC XY: 109 AN XY: 135874

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00286

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000677

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000600 AC: 873 AN: 1455110 Hom.: 3 Cov.: 27 AF XY: 0.000594 AC XY: 430 AN XY: 724366

Gnomad4 AFR exome AF: 0.000870

Gnomad4 AMR exome AF: 0.00277

Gnomad4 ASJ exome AF: 0.000345

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.000163

Gnomad4 FIN exome AF: 0.0000563

Gnomad4 NFE exome AF: 0.000492

Gnomad4 OTH exome AF: 0.00191

GnomAD4 genome AF: 0.00110 AC: 168 AN: 152298 Hom.: 1 Cov.: 32 AF XY: 0.00114 AC XY: 85 AN XY: 74470

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000706

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000968 Hom.: 0

Bravo AF: 0.00133

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000585 AC: 71

Asia WGS AF: 0.0150 AC: 52 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000771

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 19, 2022

The c.241A>G (p.I81V) alteration is located in exon 3 (coding exon 3) of the GRK4 gene. This alteration results from a A to G substitution at nucleotide position 241, causing the isoleucine (I) at amino acid position 81 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.56
DANN	Benign	0.49
DEOGEN2	Benign	0.089	.;T;.;.
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.74	T;T;T;T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.0082	T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.4	.;L;.;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.62	N;N;N;N
REVEL	Benign	0.076
Sift	Benign	0.57	T;T;T;T
Sift4G	Benign	0.53	T;T;T;T
Polyphen		0.056	B;B;B;B
Vest4		0.12
MVP		0.16
MPC		0.063
ClinPred		0.00083	T
GERP RS		1.7
Varity_R		0.15
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs142548315; hg19: chr4-2990546;