4-3004303-C-A

Variant names:

• chr4-3004303-C-A
• rs749248762
• NM_182982.3:c.412C>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_182982.3(GRK4):​c.412C>A​(p.Pro138Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign 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: 0.0000014 (0 hom.)
• Consequence: GRK4 NM_182982.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.11

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37539253).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRK4	NM_182982.3	c.412C>A	p.Pro138Thr	missense_variant	Exon 5 of 16	ENST00000398052.9	NP_892027.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRK4	ENST00000398052.9	c.412C>A	p.Pro138Thr	missense_variant	Exon 5 of 16	1	NM_182982.3	ENSP00000381129.4
GRK4	ENST00000345167.10	c.316C>A	p.Pro106Thr	missense_variant	Exon 4 of 15	1		ENSP00000264764.8
GRK4	ENST00000504933.1	c.412C>A	p.Pro138Thr	missense_variant	Exon 5 of 15	1		ENSP00000427445.1
GRK4	ENST00000398051.8	c.316C>A	p.Pro106Thr	missense_variant	Exon 4 of 14	1		ENSP00000381128.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251312 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135832

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460804 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 726778

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	.;T;.;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.75	T;T;T;T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.38	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	.;M;.;M
PrimateAI	Benign	0.30	T
PROVEAN	Pathogenic	-5.2	D;D;D;D
REVEL	Benign	0.15
Sift	Benign	0.16	T;T;T;T
Sift4G	Benign	0.48	T;T;T;T
Polyphen		0.84	P;D;P;P
Vest4		0.52
MutPred		0.49		.;Loss of glycosylation at P138 (P = 0.0224);.;Loss of glycosylation at P138 (P = 0.0224);
MVP		0.63
MPC		0.33
ClinPred		0.97	D
GERP RS		2.9
Varity_R		0.76
gMVP		0.50

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: rs749248762; hg19: chr4-3006030;