4-3013731-G-A

Variant names:

• chr4-3013731-G-A
• rs775540841
• NM_182982.3:c.644G>A

Variant summary

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

The NM_182982.3(GRK4):​c.644G>A​(p.Cys215Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,048 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: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: GRK4 NM_182982.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.69

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.833

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRK4	NM_182982.3	c.644G>A	p.Cys215Tyr	missense_variant	Exon 8 of 16	ENST00000398052.9	NP_892027.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRK4	ENST00000398052.9	c.644G>A	p.Cys215Tyr	missense_variant	Exon 8 of 16	1	NM_182982.3	ENSP00000381129.4
GRK4	ENST00000345167.10	c.548G>A	p.Cys183Tyr	missense_variant	Exon 7 of 15	1		ENSP00000264764.8
GRK4	ENST00000504933.1	c.644G>A	p.Cys215Tyr	missense_variant	Exon 8 of 15	1		ENSP00000427445.1
GRK4	ENST00000398051.8	c.548G>A	p.Cys183Tyr	missense_variant	Exon 7 of 14	1		ENSP00000381128.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000200 AC: 5 AN: 250504 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135442

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461048 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726840

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000897

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	.;T;.;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.97	D;D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.1	.;M;.;M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-9.4	D;D;D;D
REVEL	Uncertain	0.50
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		0.99	D;D;D;D
Vest4		0.86
MutPred		0.51		.;Loss of methylation at K216 (P = 0.0473);.;Loss of methylation at K216 (P = 0.0473);
MVP		0.69
MPC		0.47
ClinPred		0.94	D
GERP RS		4.7
Varity_R		0.99
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs775540841; hg19: chr4-3015458;