4-3022431-A-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP3 BP4_Moderate BS1_Supporting BS2

The NM_182982.3(GRK4):c.950A>C(p.Asn317Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000851 in 1,613,988 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00080 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00086 (10 hom.)
• Consequence: GRK4 NM_182982.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.68

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 Likely_benign. Variant got -6 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.13934132).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000857 (1252/1461658) while in subpopulation MID AF= 0.0194 (112/5768). AF 95% confidence interval is 0.0165. There are 10 homozygotes in gnomad4_exome. There are 674 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRK4	NM_182982.3	c.950A>C	p.Asn317Thr	missense_variant	10/16	ENST00000398052.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRK4	ENST00000398052.9	c.950A>C	p.Asn317Thr	missense_variant	10/16	1	NM_182982.3	P1

Frequencies

GnomAD3 genomes AF: 0.000802 AC: 122 AN: 152212 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00117 AC: 295 AN: 251126 Hom.: 2 AF XY: 0.00127 AC XY: 172 AN XY: 135722

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00183

Gnomad ASJ exome AF: 0.00883

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00108

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000765

Gnomad OTH exome AF: 0.00327

GnomAD4 exome AF: 0.000857 AC: 1252 AN: 1461658 Hom.: 10 Cov.: 30 AF XY: 0.000927 AC XY: 674 AN XY: 727124

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.00972

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00115

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000519

Gnomad4 OTH exome AF: 0.00161

GnomAD4 genome AF: 0.000801 AC: 122 AN: 152330 Hom.: 1 Cov.: 33 AF XY: 0.000779 AC XY: 58 AN XY: 74492

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00121 Hom.: 1

Bravo AF: 0.000941

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000988 AC: 120

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000655

EpiControl AF: 0.00119

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

Sep 16, 2021

The c.950A>C (p.N317T) alteration is located in exon 10 (coding exon 10) of the GRK4 gene. This alteration results from a A to C substitution at nucleotide position 950, causing the asparagine (N) at amino acid position 317 to be replaced by a threonine (T). 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	0.98
BayesDel_addAF	Benign	0.0098	T
BayesDel_noAF	Pathogenic	0.22
Cadd	Pathogenic	30
Dann	Uncertain	1.0
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.9	D;D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.026	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.97
MVP		0.98
MPC		0.39
ClinPred		0.20	T
GERP RS		5.6
Varity_R		0.99
gMVP		0.87

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: rs139428941; hg19: chr4-3024158; COSMIC: COSV61669214;