rs142478577

Variant names:

• chr4-2992275-A-C
• rs142478577
• NM_182982.3:c.322A>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_182982.3(GRK4):​c.322A>C​(p.Arg108Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00267 in 1,603,298 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (20 hom.)
• Consequence: GRK4 NM_182982.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.72
• Publications: 3 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 4-2992275-A-C is Benign according to our data. Variant chr4-2992275-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2654591.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.72 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 20 AR gene

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.322A>C	p.Arg108Arg	synonymous	Exon 4 of 16	NP_892027.2	P32298-1
	GRK4	NM_001004056.2		c.226A>C	p.Arg76Arg	synonymous	Exon 3 of 15	NP_001004056.1	P32298-2
	GRK4	NM_001004057.2		c.322A>C	p.Arg108Arg	synonymous	Exon 4 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.322A>C	p.Arg108Arg	synonymous	Exon 4 of 16	ENSP00000381129.4	P32298-1
	GRK4	ENST00000345167.10	TSL:1	c.226A>C	p.Arg76Arg	synonymous	Exon 3 of 15	ENSP00000264764.8	P32298-2
	GRK4	ENST00000504933.1	TSL:1	c.322A>C	p.Arg108Arg	synonymous	Exon 4 of 15	ENSP00000427445.1	P32298-4

Frequencies

GnomAD3 genomes AF: 0.00219 AC: 333 AN: 152204 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00300

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00289 AC: 726 AN: 251112 AF XY: 0.00341

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00844

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00157

Gnomad NFE exome AF: 0.00308

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00272 AC: 3950 AN: 1450976 Hom.: 20 Cov.: 27 AF XY: 0.00294 AC XY: 2127 AN XY: 722538

African (AFR) AF: 0.000422 AC: 14 AN: 33186

American (AMR) AF: 0.00143 AC: 64 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00861 AC: 224 AN: 26020

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.00579 AC: 498 AN: 86072

European-Finnish (FIN) AF: 0.00135 AC: 72 AN: 53204

Middle Eastern (MID) AF: 0.00750 AC: 43 AN: 5732

European-Non Finnish (NFE) AF: 0.00256 AC: 2819 AN: 1102452

Other (OTH) AF: 0.00360 AC: 216 AN: 59996

GnomAD4 genome AF: 0.00219 AC: 334 AN: 152322 Hom.: 1 Cov.: 32 AF XY: 0.00224 AC XY: 167 AN XY: 74482

African (AFR) AF: 0.000216 AC: 9 AN: 41586

American (AMR) AF: 0.00236 AC: 36 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00836 AC: 29 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00539 AC: 26 AN: 4824

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00301 AC: 205 AN: 68024

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00303 Hom.: 4

Bravo AF: 0.00235

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.50
DANN	Benign	0.46
PhyloP100		1.7
Mutation Taster		=100/0	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: rs142478577; hg19: chr4-2994002;