X-70276266-C-A

Position:

• chrX-70276266-C-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_004312.3(ARR3):​c.330C>A​(p.Tyr110*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: ARR3 NM_004312.3 stop_gained
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.0290

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-70276266-C-A is Pathogenic according to our data. Variant chrX-70276266-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3032603.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARR3	NM_004312.3	c.330C>A	p.Tyr110*	stop_gained	Exon 6 of 17	ENST00000307959.9	NP_004303.2
ARR3	XM_047442105.1	c.354C>A	p.Tyr118*	stop_gained	Exon 5 of 16		XP_047298061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARR3	ENST00000307959.9	c.330C>A	p.Tyr110*	stop_gained	Exon 6 of 17	1	NM_004312.3	ENSP00000311538.8
ARR3	ENST00000374495.7	c.330C>A	p.Tyr110*	stop_gained	Exon 6 of 16	1		ENSP00000363619.3
ARR3	ENST00000480877.6	c.177C>A	p.Tyr59*	stop_gained	Exon 6 of 8	5		ENSP00000425505.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

ARR3-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 13, 2023

The ARR3 c.330C>A variant is predicted to result in premature protein termination (p.Tyr110*). To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in ARR3 are expected to be pathogenic. We interpret this variant as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	34
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.87	D
Vest4		0.81
GERP RS		-0.94

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-69496116; COSMIC: COSV105887594;