4-3007809-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM4 BP6_Moderate BA1

The NM_182982.3(GRK4):c.517C>T(p.Gln173Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00253 in 1,611,152 control chromosomes in the GnomAD database, including 148 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Benign (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0040 (21 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (127 hom.)
• Consequence: GRK4 NM_182982.3 stop_gained
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.72

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.

• PM4: Stoplost variant in NM_182982.3 Downstream stopcodon found after 744 codons.
• BP6: Variant 4-3007809-C-T is Benign according to our data. Variant chr4-3007809-C-T is described in ClinVar as [Benign]. Clinvar id is 773153.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0678 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRK4	NM_182982.3	c.517C>T	p.Gln173Ter	stop_gained	6/16	ENST00000398052.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRK4	ENST00000398052.9	c.517C>T	p.Gln173Ter	stop_gained	6/16	1	NM_182982.3	P1
GRK4	ENST00000345167.10	c.421C>T	p.Gln141Ter	stop_gained	5/15	1
GRK4	ENST00000504933.1	c.517C>T	p.Gln173Ter	stop_gained	6/15	1
GRK4	ENST00000398051.8	c.421C>T	p.Gln141Ter	stop_gained	5/14	1

Frequencies

GnomAD3 genomes AF: 0.00394 AC: 599 AN: 152136 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0346

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00443

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.0110 AC: 2742 AN: 250128 Hom.: 109 AF XY: 0.00802 AC XY: 1084 AN XY: 135206

Gnomad AFR exome AF: 0.000802

Gnomad AMR exome AF: 0.0761

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00432

Gnomad SAS exome AF: 0.000198

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00851

GnomAD4 exome AF: 0.00237 AC: 3463 AN: 1458898 Hom.: 127 Cov.: 28 AF XY: 0.00198 AC XY: 1434 AN XY: 725854

Gnomad4 AFR exome AF: 0.000389

Gnomad4 AMR exome AF: 0.0698

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00490

Gnomad4 SAS exome AF: 0.000175

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.00196

GnomAD4 genome AF: 0.00398 AC: 606 AN: 152254 Hom.: 21 Cov.: 32 AF XY: 0.00390 AC XY: 290 AN XY: 74450

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.0350

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00444

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000693 Hom.: 5

Bravo AF: 0.00760

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00872 AC: 1059

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 30, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.66
Cadd	Pathogenic	42
Dann	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.76
GERP RS		5.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs117478149; hg19: chr4-3009536;