X-70276150-C-T

Position:

• chrX-70276150-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_004312.3(ARR3):​c.214C>T​(p.Arg72*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000273 in 1,098,141 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 1 hem.)
• Consequence: ARR3 NM_004312.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.413

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 12 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-70276150-C-T is Pathogenic according to our data. Variant chrX-70276150-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1697230.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-70276150-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARR3	NM_004312.3	c.214C>T	p.Arg72*	stop_gained	Exon 6 of 17	ENST00000307959.9	NP_004303.2
ARR3	XM_047442105.1	c.238C>T	p.Arg80*	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.214C>T	p.Arg72*	stop_gained	Exon 6 of 17	1	NM_004312.3	ENSP00000311538.8
ARR3	ENST00000374495.7	c.214C>T	p.Arg72*	stop_gained	Exon 6 of 16	1		ENSP00000363619.3
ARR3	ENST00000480877.6	c.61C>T	p.Arg21*	stop_gained	Exon 6 of 8	5		ENSP00000425505.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000273 AC: 3 AN: 1098141 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 1 AN XY: 363497

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: 0.00000356

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Myopia 26, X-linked, female-limited Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 21, 2022

- -

ARR3-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 28, 2023

The ARR3 c.214C>T variant is predicted to result in premature protein termination (p.Arg72*). This variant has been reported as segregating with disease in the female members of two large kindreds with early-onset high myopia (Széll et al. 2021. PubMed ID: 33482870; van Mazijk et al. 2022. PubMed ID: 35001458). This variant has also been reported in the heterozygous state in an additional, unrelated individual with high myopia (Table S1 in Haarman et al. 2022. PubMed ID: 35567543). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in ARR3 are expected to be pathogenic. Given the evidence, we interpret c.214C>T (p.Arg72*) as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	27
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.64	D
Vest4		0.89
GERP RS		1.4

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-69496000;