chr22-25569513-T-C

Variant names:

• chr22-25569513-T-C
• rs41258124
• NM_005160.4:c.113+4360T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005160.4(GRK3):​c.113+4360T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 152,308 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.013 (26 hom., cov: 33)
• Consequence: GRK3 NM_005160.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.270
• Publications: 1 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0537 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRK3	NM_005160.4	c.113+4360T>C		intron_variant	Intron 1 of 20	ENST00000324198.11	NP_005151.2
GRK3	NM_001362778.2	c.-153+4360T>C		intron_variant	Intron 1 of 19		NP_001349707.1
GRK3	XM_047441167.1	c.113+4360T>C		intron_variant	Intron 1 of 13		XP_047297123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRK3	ENST00000324198.11	c.113+4360T>C		intron_variant	Intron 1 of 20	1	NM_005160.4	ENSP00000317578.4
GRK3	ENST00000455558.2	n.47+4360T>C		intron_variant	Intron 1 of 8	5		ENSP00000393688.2

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1946 AN: 152190 Hom.: 25 Cov.: 33

Gnomad AFR AF: 0.00331

Gnomad AMI AF: 0.0822

Gnomad AMR AF: 0.0112

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.00327

Gnomad SAS AF: 0.0585

Gnomad FIN AF: 0.00932

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0150

Gnomad OTH AF: 0.0143

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0128 AC: 1950 AN: 152308 Hom.: 26 Cov.: 33 AF XY: 0.0128 AC XY: 955 AN XY: 74482

African (AFR) AF: 0.00330 AC: 137 AN: 41574

American (AMR) AF: 0.0112 AC: 171 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0271 AC: 94 AN: 3470

East Asian (EAS) AF: 0.00309 AC: 16 AN: 5180

South Asian (SAS) AF: 0.0593 AC: 286 AN: 4820

European-Finnish (FIN) AF: 0.00932 AC: 99 AN: 10624

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0150 AC: 1022 AN: 68020

Other (OTH) AF: 0.0147 AC: 31 AN: 2114

Alfa AF: 0.0141 Hom.: 1

Bravo AF: 0.0120

Asia WGS AF: 0.0280 AC: 98 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.2
DANN	Benign	0.52
PhyloP100		0.27
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: rs41258124; hg19: chr22-25965480;