Variant X-70270131-A-C 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.132A>C(p.Leu44Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,209,464 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 50 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.00013 ( 0 hom. 48 hem. )

Consequence

ARR3
NM_004312.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.42

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=0.25566053).

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARR3	NM_004312.3 linkuse as main transcript	c.132A>C	p.Leu44Phe	missense_variant	5/17	ENST00000307959.9
ARR3	XM_047442105.1 linkuse as main transcript	c.156A>C	p.Leu52Phe	missense_variant	4/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARR3	ENST00000307959.9 linkuse as main transcript	c.132A>C	p.Leu44Phe	missense_variant	5/17	1	NM_004312.3	P1	P36575-1
ARR3	ENST00000374495.7 linkuse as main transcript	c.132A>C	p.Leu44Phe	missense_variant	5/16	1			P36575-2
ARR3	ENST00000480877.6 linkuse as main transcript	c.-22A>C		5_prime_UTR_variant	5/8	5

Frequencies

GnomAD3 genomes

AF:

0.0000534

AC:

AN:

112395

Hom.:

Cov.:

AF XY:

0.0000579

AC XY:

AN XY:

34549

show subpopulations

Gnomad AFR

AF:

0.0000647

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:

0.0000750

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000382

AC:

AN:

183396

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67838

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:

0.0000733

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.000129

AC:

142

AN:

1097069

Hom.:

Cov.:

AF XY:

0.000132

AC XY:

AN XY:

362443

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

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:

0.000155

Gnomad4 OTH exome

AF:

0.000239

GnomAD4 genome

AF:

0.0000534

AC:

AN:

112395

Hom.:

Cov.:

AF XY:

0.0000579

AC XY:

AN XY:

34549

show subpopulations

Gnomad4 AFR

AF:

0.0000647

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:

0.0000750

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000907

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

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

Jan 17, 2023

The c.132A>C (p.L44F) alteration is located in exon 5 (coding exon 4) of the ARR3 gene. This alteration results from a A to C substitution at nucleotide position 132, causing the leucine (L) at amino acid position 44 to be replaced by a phenylalanine (F). 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

0.20

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.96

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.26

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;.;L

MutationTaster

Benign

0.85

N;N

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-2.6

D;.;D

REVEL

Benign

0.10

Sift

Benign

0.060

T;.;T

Sift4G

Uncertain

0.041

D;D;D

Polyphen

0.080

B;.;P

Vest4

0.38

MutPred

0.21

Gain of catalytic residue at L44 (P = 0.0174);Gain of catalytic residue at L44 (P = 0.0174);Gain of catalytic residue at L44 (P = 0.0174);

MVP

0.61

MPC

0.33

ClinPred

0.12

GERP RS

0.45

Varity_R

0.18

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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