Variant X-70270135-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004312.3(ARR3):c.136T>A(p.Cys46Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000456 in 1,096,738 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 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 (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000046 ( 0 hom. 1 hem. )

Consequence

ARR3
NM_004312.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.29

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19784674).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARR3	NM_004312.3 link	c.136T>A	p.Cys46Ser	missense_variant	Exon 5 of 17	ENST00000307959.9	NP_004303.2	P36575-1
ARR3	XM_047442105.1 link	c.160T>A	p.Cys54Ser	missense_variant	Exon 4 of 16		XP_047298061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ARR3	ENST00000307959.9 link	c.136T>A	p.Cys46Ser	missense_variant	Exon 5 of 17	1	NM_004312.3	ENSP00000311538.8	P36575-1
ARR3	ENST00000374495.7 link	c.136T>A	p.Cys46Ser	missense_variant	Exon 5 of 16	1		ENSP00000363619.3	P36575-2
ARR3	ENST00000480877 link	c.-18T>A		5_prime_UTR_variant	Exon 5 of 8	5		ENSP00000425505.1	D6RCT3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000456

AC:

AN:

1096738

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

362118

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:

0.00000476

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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

Dec 10, 2024

The c.136T>A (p.C46S) alteration is located in exon 5 (coding exon 4) of the ARR3 gene. This alteration results from a T to A substitution at nucleotide position 136, causing the cysteine (C) at amino acid position 46 to be replaced by a serine (S). 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

0.060

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.93

CADD

Benign

DANN

Benign

0.62

DEOGEN2

Benign

0.074

.;.;T

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.67

T;T;T

M_CAP

Benign

0.0040

MetaRNN

Benign

0.20

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.55

N;.;N

PrimateAI

Benign

0.34

PROVEAN

Benign

2.6

N;.;N

REVEL

Benign

0.071

Sift

Benign

0.087

T;.;T

Sift4G

Benign

0.23

T;T;T

Polyphen

0.0

B;.;B

Vest4

0.14

MutPred

0.50

Loss of methylation at K45 (P = 0.0223);Loss of methylation at K45 (P = 0.0223);Loss of methylation at K45 (P = 0.0223);

MVP

0.50

MPC

0.090

ClinPred

0.60

GERP RS

3.3

Varity_R

0.11

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over