NM_005160.4:c.335A>C

Variant names:

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

Variant summary

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

The NM_005160.4(GRK3):​c.335A>C​(p.Tyr112Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GRK3 NM_005160.4 missense
• Clinical Significance: Not reported in ClinVar
• 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, 0.792

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRK3	NM_005160.4	c.335A>C	p.Tyr112Ser	missense_variant	Exon 4 of 21	ENST00000324198.11	NP_005151.2
GRK3	XM_047441166.1	c.230A>C	p.Tyr77Ser	missense_variant	Exon 4 of 21		XP_047297122.1
GRK3	XM_047441167.1	c.335A>C	p.Tyr112Ser	missense_variant	Exon 4 of 14		XP_047297123.1
GRK3	NM_001362778.2	c.-5A>C		5_prime_UTR_variant	Exon 3 of 20		NP_001349707.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRK3	ENST00000324198.11	c.335A>C	p.Tyr112Ser	missense_variant	Exon 4 of 21	1	NM_005160.4	ENSP00000317578.4
GRK3	ENST00000455558.2	n.*57A>C		non_coding_transcript_exon_variant	Exon 3 of 9	5		ENSP00000393688.2
GRK3	ENST00000455558.2	n.*57A>C		3_prime_UTR_variant	Exon 3 of 9	5		ENSP00000393688.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459468 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T;T
Eigen	Benign	0.089
Eigen_PC	Benign	0.053
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.7	D;.
REVEL	Benign	0.18
Sift	Uncertain	0.0040	D;.
Sift4G	Benign	0.064	T;T
Polyphen		0.61	P;.
Vest4		0.82
MutPred		0.67		Gain of disorder (P = 0.0049);Gain of disorder (P = 0.0049);
MVP		0.043
MPC		1.6
ClinPred		0.94	D
GERP RS		3.6
Varity_R		0.47
gMVP		0.79

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-26057613;