Variant X-70276708-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004312.3(ARR3):c.445G>A(p.Glu149Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000827 in 1,209,850 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.0000082 ( 0 hom. 3 hem. )

Consequence

ARR3
NM_004312.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.51

Variant links:

Genes affected

ARR3 (HGNC:710): (arrestin 3) The protein encoded by this gene is a non-visual arrestin which binds to agonist-activated, phosphorylated G protein-coupled receptors. This binding uncouples the receptor from the heterotrimeric G protein, resulting in termination of the G protein-coupled receptor signaling. The encoded protein also is a part of the centrosome, interacting with gamma-tubulin to help regulate proper centrosome function. [provided by RefSeq, May 2016]

ARR3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.22420293).

BS2

High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARR3	NM_004312.3 link	c.445G>A	p.Glu149Lys	missense_variant	Exon 8 of 17	ENST00000307959.9	NP_004303.2	P36575-1
ARR3	XM_047442105.1 link	c.469G>A	p.Glu157Lys	missense_variant	Exon 7 of 16		XP_047298061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ARR3	ENST00000307959.9 link	c.445G>A	p.Glu149Lys	missense_variant	Exon 8 of 17	1	NM_004312.3	ENSP00000311538.8	P36575-1
ARR3	ENST00000374495.7 link	c.445G>A	p.Glu149Lys	missense_variant	Exon 8 of 16	1		ENSP00000363619.3	P36575-2
ARR3	ENST00000480877.6 link	c.*1G>A		downstream_gene_variant		5		ENSP00000425505.1	D6RCT3

Frequencies

GnomAD3 genomes

AF:

0.00000893

AC:

AN:

111967

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

34117

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000547

AC:

AN:

182978

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67426

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000820

AC:

AN:

1097883

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

363241

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000950

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.00000893

AC:

AN:

111967

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

34117

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 12, 2024

The c.445G>A (p.E149K) alteration is located in exon 8 (coding exon 7) of the ARR3 gene. This alteration results from a G to A substitution at nucleotide position 445, causing the glutamic acid (E) at amino acid position 149 to be replaced by a lysine (K). 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

0.083

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.85

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

.;.;T

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.22

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;.;L

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-2.4

N;.;N

REVEL

Benign

0.062

Sift

Benign

0.21

T;.;T

Sift4G

Benign

0.24

T;T;T

Polyphen

0.73

P;.;D

Vest4

0.14

MutPred

0.51

Gain of methylation at E149 (P = 0.0115);Gain of methylation at E149 (P = 0.0115);Gain of methylation at E149 (P = 0.0115);

MVP

0.29

MPC

0.35

ClinPred

0.76

GERP RS

3.2

Varity_R

0.28

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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