4-3004303-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_182982.3(GRK4):​c.412C>G​(p.Pro138Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P138S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRK4 NM_182982.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.11
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16600353).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182982.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRK4	NM_182982.3	MANE Select	c.412C>G	p.Pro138Ala	missense	Exon 5 of 16	NP_892027.2	P32298-1
	GRK4	NM_001004056.2		c.316C>G	p.Pro106Ala	missense	Exon 4 of 15	NP_001004056.1	P32298-2
	GRK4	NM_001004057.2		c.412C>G	p.Pro138Ala	missense	Exon 5 of 15	NP_001004057.1	P32298-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRK4	ENST00000398052.9	TSL:1 MANE Select	c.412C>G	p.Pro138Ala	missense	Exon 5 of 16	ENSP00000381129.4	P32298-1
	GRK4	ENST00000345167.10	TSL:1	c.316C>G	p.Pro106Ala	missense	Exon 4 of 15	ENSP00000264764.8	P32298-2
	GRK4	ENST00000504933.1	TSL:1	c.412C>G	p.Pro138Ala	missense	Exon 5 of 15	ENSP00000427445.1	P32298-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.1
PrimateAI	Benign	0.29	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Benign	0.14
Sift	Benign	0.34	T
Sift4G	Benign	0.74	T
Polyphen		0.77	P
Vest4		0.21
MutPred		0.52		Loss of glycosylation at P138 (P = 0.016)
MVP		0.59
MPC		0.17
ClinPred		0.91	D
GERP RS		2.9
Varity_R		0.59
gMVP		0.40
Mutation Taster		=75/25	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: rs749248762; hg19: chr4-3006030;