chr4-2984578-A-C

Position:

• chr4-2984578-A-C

Variant summary

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

The NM_182982.3(GRK4):​c.118A>C​(p.Ser40Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRK4 NM_182982.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.16

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, 0.775

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRK4	NM_182982.3	c.118A>C	p.Ser40Arg	missense_variant	2/16	ENST00000398052.9	NP_892027.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRK4	ENST00000398052.9	c.118A>C	p.Ser40Arg	missense_variant	2/16	1	NM_182982.3	ENSP00000381129	P1
GRK4	ENST00000504933.1	c.118A>C	p.Ser40Arg	missense_variant	2/15	1		ENSP00000427445
GRK4	ENST00000345167.10	c.53-4149A>C		intron_variant		1		ENSP00000264764
GRK4	ENST00000398051.8	c.53-4149A>C		intron_variant		1		ENSP00000381128

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2023

The c.118A>C (p.S40R) alteration is located in exon 2 (coding exon 2) of the GRK4 gene. This alteration results from a A to C substitution at nucleotide position 118, causing the serine (S) at amino acid position 40 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.012	T
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Benign	0.12
Sift	Benign	0.095	T;T
Sift4G	Benign	0.14	T;T
Polyphen		1.0	D;D
Vest4		0.75
MutPred		0.23		Gain of catalytic residue at S40 (P = 0.0211);Gain of catalytic residue at S40 (P = 0.0211);
MVP		0.86
MPC		0.37
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.65
gMVP		0.44

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-2986305;