NM_005160.4:c.335A>G

Variant names:

• chr22-25661646-A-G
• rs2084910322
• NM_005160.4:c.335A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005160.4(GRK3):​c.335A>G​(p.Tyr112Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,459,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GRK3 NM_005160.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.32

Genes affected

GRK3 (HGNC:290): (G protein-coupled receptor kinase 3) The beta-adrenergic receptor kinase specifically phosphorylates the agonist-occupied form of the beta-adrenergic and related G protein-coupled receptors. Overall, the beta adrenergic receptor kinase 2 has 85% amino acid similarity with beta adrenergic receptor kinase 1, with the protein kinase catalytic domain having 95% similarity. These data suggest the existence of a family of receptor kinases which may serve broadly to regulate receptor function. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.821

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRK3	NM_005160.4	c.335A>G	p.Tyr112Cys	missense_variant	Exon 4 of 21	ENST00000324198.11	NP_005151.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRK3	ENST00000324198.11	c.335A>G	p.Tyr112Cys	missense_variant	Exon 4 of 21	1	NM_005160.4	ENSP00000317578.4
GRK3	ENST00000455558.2	n.*57A>G		non_coding_transcript_exon_variant	Exon 3 of 9	5		ENSP00000393688.2
GRK3	ENST00000455558.2	n.*57A>G		3_prime_UTR_variant	Exon 3 of 9	5		ENSP00000393688.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459468 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 726114

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.335A>G (p.Y112C) alteration is located in exon 4 (coding exon 4) of the GRK3 gene. This alteration results from a A to G substitution at nucleotide position 335, causing the tyrosine (Y) at amino acid position 112 to be replaced by a cysteine (C). 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	0.12
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.013	T
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-4.0	D;.
REVEL	Benign	0.20
Sift	Uncertain	0.0020	D;.
Sift4G	Benign	0.095	T;T
Polyphen		0.99	D;.
Vest4		0.85
MutPred		0.67		Loss of phosphorylation at Y112 (P = 0.0533);Loss of phosphorylation at Y112 (P = 0.0533);
MVP		0.068
MPC		0.82
ClinPred		0.94	D
GERP RS		3.6
Varity_R		0.40
gMVP		0.76

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: rs2084910322; hg19: chr22-26057613;