4-3007809-C-T

Variant names:

• chr4-3007809-C-T
• rs117478149
• NM_182982.3:c.517C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_182982.3(GRK4):​c.517C>T​(p.Gln173*) 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.72
• Publications: 6 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]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 4-3007809-C-T is Benign according to our data. Variant chr4-3007809-C-T is described in ClinVar as Benign. ClinVar VariationId is 773153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0678 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRK4	NM_182982.3	MANE Select	c.517C>T	p.Gln173*	stop_gained	Exon 6 of 16	NP_892027.2	P32298-1
	GRK4	NM_001004056.2		c.421C>T	p.Gln141*	stop_gained	Exon 5 of 15	NP_001004056.1	P32298-2
	GRK4	NM_001004057.2		c.517C>T	p.Gln173*	stop_gained	Exon 6 of 15	NP_001004057.1	P32298-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRK4	ENST00000398052.9	TSL:1 MANE Select	c.517C>T	p.Gln173*	stop_gained	Exon 6 of 16	ENSP00000381129.4	P32298-1
	GRK4	ENST00000345167.10	TSL:1	c.421C>T	p.Gln141*	stop_gained	Exon 5 of 15	ENSP00000264764.8	P32298-2
	GRK4	ENST00000504933.1	TSL:1	c.517C>T	p.Gln173*	stop_gained	Exon 6 of 15	ENSP00000427445.1	P32298-4

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

GnomAD2 exomes AF: 0.0110 AC: 2742 AN: 250128 AF XY: 0.00802

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 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

African (AFR) AF: 0.000389 AC: 13 AN: 33414

American (AMR) AF: 0.0698 AC: 3094 AN: 44296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00490 AC: 194 AN: 39582

South Asian (SAS) AF: 0.000175 AC: 15 AN: 85808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000261 AC: 29 AN: 1110318

Other (OTH) AF: 0.00196 AC: 118 AN: 60264

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

African (AFR) AF: 0.000866 AC: 36 AN: 41550

American (AMR) AF: 0.0350 AC: 535 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00444 AC: 23 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68028

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00172 Hom.: 33

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		7.7
Vest4		0.76
GERP RS		5.8
Mutation Taster		=130/70	polymorphism (auto)

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

Other links and lift over

dbSNP: rs117478149; hg19: chr4-3009536;