chr4-3019722-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_182982.3(GRK4):​c.823C>T​(p.His275Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. 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

Scores

11
3
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.72
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.92

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GRK4NM_182982.3 linkuse as main transcriptc.823C>T p.His275Tyr missense_variant 9/16 ENST00000398052.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GRK4ENST00000398052.9 linkuse as main transcriptc.823C>T p.His275Tyr missense_variant 9/161 NM_182982.3 P1P32298-1
GRK4ENST00000345167.10 linkuse as main transcriptc.727C>T p.His243Tyr missense_variant 8/151 P32298-2
GRK4ENST00000504933.1 linkuse as main transcriptc.823C>T p.His275Tyr missense_variant 9/151 P32298-4
GRK4ENST00000398051.8 linkuse as main transcriptc.727C>T p.His243Tyr missense_variant 8/141 P32298-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 27, 2022The c.823C>T (p.H275Y) alteration is located in exon 9 (coding exon 9) of the GRK4 gene. This alteration results from a C to T substitution at nucleotide position 823, causing the histidine (H) at amino acid position 275 to be replaced by a tyrosine (Y). 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
Pathogenic
0.69
BayesDel_addAF
Pathogenic
0.29
D
BayesDel_noAF
Pathogenic
0.18
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.36
.;T;.;.
Eigen
Pathogenic
0.70
Eigen_PC
Pathogenic
0.72
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.99
D;D;D;D
M_CAP
Benign
0.028
D
MetaRNN
Pathogenic
0.92
D;D;D;D
MetaSVM
Benign
-0.33
T
MutationAssessor
Benign
0.98
.;L;.;L
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.67
T
PROVEAN
Pathogenic
-5.8
D;D;D;D
REVEL
Uncertain
0.63
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D
Polyphen
1.0
D;D;D;D
Vest4
0.89
MutPred
0.73
.;Loss of methylation at K273 (P = 0.1356);.;Loss of methylation at K273 (P = 0.1356);
MVP
0.80
MPC
0.40
ClinPred
1.0
D
GERP RS
5.2
Varity_R
0.95
gMVP
0.73

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: chr4-3021449; COSMIC: COSV61669293; COSMIC: COSV61669293; API