X-70280804-C-T

Position:

chrX-70280804-C-T

Variant summary

Our verdict is Likely benign. Variant got -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).

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

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 -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 id is 221943.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High Hemizygotes in GnomAd4 at 12 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARR3	NM_004312.3 linkuse as main transcript	c.1052C>T	p.Pro351Leu	missense_variant	15/17	ENST00000307959.9	NP_004303.2	P36575-1
ARR3	XM_047442105.1 linkuse as main transcript	c.1076C>T	p.Pro359Leu	missense_variant	14/16		XP_047298061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARR3	ENST00000307959.9 linkuse as main transcript	c.1052C>T	p.Pro351Leu	missense_variant	15/17	1	NM_004312.3	ENSP00000311538.8		P36575-1
ARR3	ENST00000374495.7 linkuse as main transcript	c.1052C>T	p.Pro351Leu	missense_variant	15/16	1		ENSP00000363619.3		P36575-2

Frequencies

GnomAD3 genomes

AF:

0.000415

AC:

AN:

110960

Hom.:

Cov.:

AF XY:

0.000362

AC XY:

AN XY:

33162

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

GnomAD3 exomes

AF:

0.000425

AC:

AN:

183385

Hom.:

AF XY:

0.000383

AC XY:

AN XY:

67821

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 SAS 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

Gnomad4 AFR exome

AF:

0.000114

Gnomad4 AMR exome

AF:

0.000256

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000369

Gnomad4 FIN exome

AF:

0.000173

Gnomad4 NFE exome

AF:

0.000575

Gnomad4 OTH exome

AF:

0.000304

GnomAD4 genome

AF:

0.000415

AC:

AN:

110960

Hom.:

Cov.:

AF XY:

0.000362

AC XY:

AN XY:

33162

show subpopulations

Gnomad4 AFR

AF:

0.000296

Gnomad4 AMR

AF:

0.000191

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000661

Gnomad4 OTH

AF:

0.00

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

Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 02, 2021	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

Likely benign, criteria provided, single submitter

clinical testing

Paul Sabatier University EA-4555, Paul Sabatier University

Jan 01, 2013

- -

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

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

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

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

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