X-70270102-G-A

Position:

• chrX-70270102-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004312.3(ARR3):​c.103G>A​(p.Gly35Ser) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: ARR3 NM_004312.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 4.41

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARR3	NM_004312.3	c.103G>A	p.Gly35Ser	missense_variant, splice_region_variant	Exon 5 of 17	ENST00000307959.9	NP_004303.2
ARR3	XM_047442105.1	c.127G>A	p.Gly43Ser	missense_variant	Exon 4 of 16		XP_047298061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARR3	ENST00000307959.9	c.103G>A	p.Gly35Ser	missense_variant, splice_region_variant	Exon 5 of 17	1	NM_004312.3	ENSP00000311538.8
ARR3	ENST00000374495.7	c.103G>A	p.Gly35Ser	missense_variant, splice_region_variant	Exon 5 of 16	1		ENSP00000363619.3
ARR3	ENST00000480877.6	c.-51G>A		splice_region_variant	Exon 5 of 8	5		ENSP00000425505.1
ARR3	ENST00000480877	c.-51G>A		5_prime_UTR_variant	Exon 5 of 8	5		ENSP00000425505.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 16, 2023

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with ARR3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 35 of the ARR3 protein (p.Gly35Ser). -

ARR3-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 18, 2024

The ARR3 c.103G>A variant is predicted to result in the amino acid substitution p.Gly35Ser. This variant has been reported de novo in a female individual with early-onset high myopia (Wang et al. 2023. PubMed ID: 36180177). This variant has not been reported in a large population database, indicating this variant is rare. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	.;.;T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	-0.064	T
MutationAssessor	Pathogenic	3.4	M;.;M
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-5.0	D;.;D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.85
MutPred		0.93		Loss of catalytic residue at V36 (P = 0.0694);Loss of catalytic residue at V36 (P = 0.0694);Loss of catalytic residue at V36 (P = 0.0694);
MVP		0.72
MPC		0.43
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.89
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.25		Position offset: -2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-69489952; COSMIC: COSV104411212; COSMIC: COSV104411212;