rs765658563

Positions:

• chrX-70278629-C-A
• chrX-70278629-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_004312.3(ARR3):​c.893C>A​(p.Ala298Asp) variant causes a missense 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: ARR3 NM_004312.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.39

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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946
• PP5: Variant X-70278629-C-A is Pathogenic according to our data. Variant chrX-70278629-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 478824.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-70278629-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARR3	NM_004312.3	c.893C>A	p.Ala298Asp	missense_variant	12/17	ENST00000307959.9	NP_004303.2
ARR3	XM_047442105.1	c.917C>A	p.Ala306Asp	missense_variant	11/16		XP_047298061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARR3	ENST00000307959.9	c.893C>A	p.Ala298Asp	missense_variant	12/17	1	NM_004312.3	ENSP00000311538	P1
ARR3	ENST00000374495.7	c.893C>A	p.Ala298Asp	missense_variant	12/16	1		ENSP00000363619

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

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
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	.;.;T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Benign	0.064	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.8	M;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.6	D;.;D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.88
MutPred		0.82		Gain of disorder (P = 0.0273);Gain of disorder (P = 0.0273);Gain of disorder (P = 0.0273);
MVP		0.64
MPC		0.49
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.96
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs765658563; hg19: chrX-69498479;