22-25604424-C-A

Variant names:

• chr22-25604424-C-A
• rs1000738501
• NM_005160.4:c.161C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005160.4(GRK3):​c.161C>A​(p.Thr54Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 152,292 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: GRK3 NM_005160.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.89

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRK3	NM_005160.4	c.161C>A	p.Thr54Asn	missense_variant	Exon 2 of 21	ENST00000324198.11	NP_005151.2
GRK3	XM_047441166.1	c.56C>A	p.Thr19Asn	missense_variant	Exon 2 of 21		XP_047297122.1
GRK3	XM_047441167.1	c.161C>A	p.Thr54Asn	missense_variant	Exon 2 of 14		XP_047297123.1
GRK3	NM_001362778.2	c.-105C>A		5_prime_UTR_variant	Exon 2 of 20		NP_001349707.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRK3	ENST00000324198.11	c.161C>A	p.Thr54Asn	missense_variant	Exon 2 of 21	1	NM_005160.4	ENSP00000317578.4
GRK3	ENST00000455558.2	n.95C>A		non_coding_transcript_exon_variant	Exon 2 of 9	5		ENSP00000393688.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74470

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	T;T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.052
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.0068	T
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.3	L;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.55	N;.
REVEL	Benign	0.13
Sift	Benign	0.54	T;.
Sift4G	Benign	0.66	T;T
Polyphen		0.070	B;.
Vest4		0.90
MVP		0.043
MPC		0.62
ClinPred		0.89	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.52

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: rs1000738501; hg19: chr22-26000391;