Variant 3-141807646-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_139209.3(GRK7):c.1052C>A(p.Ala351Asp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

GRK7
NM_139209.3 missense, splice_region

Scores

Splicing: ADA: 0.6945

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.48

Variant links:

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]

GRK7 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.939

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRK7	NM_139209.3 linkuse as main transcript	c.1052C>A	p.Ala351Asp	missense_variant, splice_region_variant	5/6	ENST00000682958.1
GRK7	XM_047447449.1 linkuse as main transcript	c.1052C>A	p.Ala351Asp	missense_variant, splice_region_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRK7	ENST00000682958.1 linkuse as main transcript	c.1052C>A	p.Ala351Asp	missense_variant, splice_region_variant	5/6		NM_139209.3	P1
GRK7	ENST00000264952.2 linkuse as main transcript	c.1052C>A	p.Ala351Asp	missense_variant, splice_region_variant	3/4	1		P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000678

AC:

AN:

250890

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135646

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000463

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:

0.0000109

AC:

AN:

1461276

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726926

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000358

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:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000659

AC:

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 submitter

clinical testing

Ambry Genetics

Aug 28, 2021

The c.1052C>A (p.A351D) alteration is located in exon 3 (coding exon 3) of the GRK7 gene. This alteration results from a C to A substitution at nucleotide position 1052, causing the alanine (A) at amino acid position 351 to be replaced by an aspartic acid (D). 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

0.99

BayesDel_addAF

Uncertain

0.079

BayesDel_noAF

Pathogenic

0.22

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Benign

0.23

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.081

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

-0.050

MutationAssessor

Benign

1.9

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-4.0

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.011

Polyphen

1.0

Vest4

0.97

MutPred

0.85

Gain of disorder (P = 0.0432);

MVP

0.92

MPC

1.1

ClinPred

0.81

GERP RS

3.7

Varity_R

0.94

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.69

dbscSNV1_RF

Pathogenic

0.75

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over