NM_004312.3:c.1052C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_004312.3(ARR3):c.1052C>T(p.Pro351Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000469 in 1,209,093 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 182 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P351R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., 12 hem., cov: 21)

Exomes 𝑓: 0.00047 ( 0 hom. 170 hem. )

Consequence

ARR3
NM_004312.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 6.82

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

myopia 26, X-linked, female-limited
Inheritance: XL Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ARR3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP6

Variant X-70280804-C-T is Benign according to our data. Variant chrX-70280804-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 221943.

BS2

High Hemizygotes in GnomAd4 at 12 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARR3	NM_004312.3 link	c.1052C>T	p.Pro351Leu	missense_variant	Exon 15 of 17	ENST00000307959.9	NP_004303.2	P36575-1
ARR3	XM_047442105.1 link	c.1076C>T	p.Pro359Leu	missense_variant	Exon 14 of 16		XP_047298061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARR3	ENST00000307959.9 link	c.1052C>T	p.Pro351Leu	missense_variant	Exon 15 of 17	1	NM_004312.3	ENSP00000311538.8		P36575-1
ARR3	ENST00000374495.7 link	c.1052C>T	p.Pro351Leu	missense_variant	Exon 15 of 16	1		ENSP00000363619.3		P36575-2

Frequencies

GnomAD3 genomes

AF:

0.000415

AC:

AN:

110960

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000296

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000191

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:

0.000661

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000425

AC:

AN:

183385

AF XY:

0.000383

show subpopulations

Gnomad AFR exome

AF:

0.000380

Gnomad AMR exome

AF:

0.000328

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000188

Gnomad NFE exome

AF:

0.000745

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000474

AC:

521

AN:

1098133

Hom.:

Cov.:

AF XY:

0.000468

AC XY:

170

AN XY:

363519

show subpopulations

African (AFR)

AF:

0.000114

AC:

AN:

26395

American (AMR)

AF:

0.000256

AC:

AN:

35202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19384

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.0000369

AC:

AN:

54141

European-Finnish (FIN)

AF:

0.000173

AC:

AN:

40527

Middle Eastern (MID)

AF:

0.000486

AC:

AN:

4116

European-Non Finnish (NFE)

AF:

0.000575

AC:

484

AN:

842076

Other (OTH)

AF:

0.000304

AC:

AN:

46086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

116

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000415

AC:

AN:

110960

Hom.:

Cov.:

AF XY:

0.000362

AC XY:

AN XY:

33162

show subpopulations

African (AFR)

AF:

0.000296

AC:

AN:

30418

American (AMR)

AF:

0.000191

AC:

AN:

10460

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2634

East Asian (EAS)

AF:

0.00

AC:

AN:

3522

South Asian (SAS)

AF:

0.00

AC:

AN:

2578

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6010

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.000661

AC:

AN:

52924

Other (OTH)

AF:

0.00

AC:

AN:

1493

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000182

Hom.:

Bravo

AF:

0.000476

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000395

AC:

EpiCase

AF:

0.000818

EpiControl

AF:

0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 02, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline with leucine at codon 351 of the ARR3 protein (p.Pro351Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs140505250, ExAC 0.06%). This variant has not been reported in the literature in individuals affected with ARR3-related conditions. ClinVar contains an entry for this variant (Variation ID: 221943). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Anophthalmia-microphthalmia syndrome

Benign:1

Jan 01, 2013

Paul Sabatier University EA-4555, Paul Sabatier University

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

0.00092

BayesDel_noAF

Pathogenic

0.14

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

.;.;T

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.86

D;D;D

M_CAP

Benign

0.077

MetaRNN

Uncertain

0.63

D;D;D

MetaSVM

Benign

-0.50

MutationAssessor

Pathogenic

3.2

M;.;M

PhyloP100

6.8

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-8.5

D;.;D

REVEL

Uncertain

0.55

Sift

Pathogenic

0.0

D;.;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.74

MVP

0.89

MPC

0.44

ClinPred

0.19

GERP RS

4.8

Varity_R

0.91

gMVP

0.78

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over