4-3009652-C-A

Variant names:

• chr4-3009652-C-A
• NM_182982.3:c.541C>A

Variant summary

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

The NM_182982.3(GRK4):​c.541C>A​(p.Pro181Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,826 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GRK4 NM_182982.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.88

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

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
GRK4	NM_182982.3	c.541C>A	p.Pro181Thr	missense_variant	Exon 7 of 16	ENST00000398052.9	NP_892027.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRK4	ENST00000398052.9	c.541C>A	p.Pro181Thr	missense_variant	Exon 7 of 16	1	NM_182982.3	ENSP00000381129.4
GRK4	ENST00000345167.10	c.445C>A	p.Pro149Thr	missense_variant	Exon 6 of 15	1		ENSP00000264764.8
GRK4	ENST00000504933.1	c.541C>A	p.Pro181Thr	missense_variant	Exon 7 of 15	1		ENSP00000427445.1
GRK4	ENST00000398051.8	c.445C>A	p.Pro149Thr	missense_variant	Exon 6 of 14	1		ENSP00000381128.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460826 Hom.: 0 Cov.: 29 AF XY: 0.00000413 AC XY: 3 AN XY: 726802

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: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	.;D;.;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.48	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	.;M;.;M
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-7.2	D;D;D;D
REVEL	Benign	0.25
Sift	Uncertain	0.021	D;D;D;D
Sift4G	Uncertain	0.031	D;D;D;D
Polyphen		0.99	D;D;P;D
Vest4		0.53
MutPred		0.38		.;Gain of MoRF binding (P = 0.0699);.;Gain of MoRF binding (P = 0.0699);
MVP		0.46
MPC		0.36
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.97
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr4-3011379;