3-141778837-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_139209.3(GRK7):c.553C>T(p.Pro185Ser) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRK7 NM_139209.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.55

Genes affected

GRK7 (HGNC:17031): (G protein-coupled receptor kinase 7) This gene encodes a member of the guanine nucleotide-binding protein (G protein)-coupled receptor kinase subfamily of the Ser/Thr protein kinase family. It is specifically expressed in the retina and the encoded protein has been shown to phosphorylate cone opsins and initiate their deactivation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3828197).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRK7	NM_139209.3	c.553C>T	p.Pro185Ser	missense_variant	3/6	ENST00000682958.1
GRK7	XM_047447449.1	c.553C>T	p.Pro185Ser	missense_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRK7	ENST00000682958.1	c.553C>T	p.Pro185Ser	missense_variant	3/6		NM_139209.3	P1
GRK7	ENST00000264952.2	c.553C>T	p.Pro185Ser	missense_variant	1/4	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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 14, 2023

The c.553C>T (p.P185S) alteration is located in exon 1 (coding exon 1) of the GRK7 gene. This alteration results from a C to T substitution at nucleotide position 553, causing the proline (P) at amino acid position 185 to be replaced by a serine (S). 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	0.14
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.078
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	0.90	D
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Benign	0.14
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.028	D
Polyphen		0.48	P
Vest4		0.47
MutPred		0.46		Loss of ubiquitination at K189 (P = 0.1647);
MVP		0.59
MPC		0.45
ClinPred		0.98	D
GERP RS		4.2
Varity_R		0.43
gMVP		0.48

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: rs1225198061; hg19: chr3-141497679;