rs1555941129

Positions:

• chrX-70276234-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 9P and 4B. PVS1 PP5 BS2

The NM_004312.3(ARR3):​c.298C>T​(p.Arg100Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000638 in 1,098,025 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000064 (0 hom. 3 hem.)
• Consequence: ARR3 NM_004312.3 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.251

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 Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant X-70276234-C-T is Pathogenic according to our data. Variant chrX-70276234-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 478825.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-70276234-C-T is described in Lovd as [Pathogenic].
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARR3	NM_004312.3	c.298C>T	p.Arg100Ter	stop_gained	6/17	ENST00000307959.9	NP_004303.2
ARR3	XM_047442105.1	c.322C>T	p.Arg108Ter	stop_gained	5/16		XP_047298061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARR3	ENST00000307959.9	c.298C>T	p.Arg100Ter	stop_gained	6/17	1	NM_004312.3	ENSP00000311538	P1
ARR3	ENST00000374495.7	c.298C>T	p.Arg100Ter	stop_gained	6/16	1		ENSP00000363619
ARR3	ENST00000480877.6	c.145C>T	p.Arg49Ter	stop_gained	6/8	5		ENSP00000425505

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000638 AC: 7 AN: 1098025 Hom.: 0 Cov.: 32 AF XY: 0.00000826 AC XY: 3 AN XY: 363383

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: 0.00000831

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 22, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	30
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.17	N
MutationTaster	Benign	1.0	A;A
Vest4		0.85
GERP RS		1.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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

Other links and lift over

dbSNP: rs1555941129; hg19: chrX-69496084; COSMIC: COSV57205877;