X-70281744-C-A

Position:

• chrX-70281744-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004312.3(ARR3):​c.1145C>A​(p.Ala382Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000019 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: ARR3 NM_004312.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.632

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]

PDZD11 (HGNC:28034): (PDZ domain containing 11) Enables protein C-terminus binding activity. Involved in pore complex assembly. Located in basolateral plasma membrane and cytosol. Part of pore complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.059346914).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARR3	NM_004312.3	c.1145C>A	p.Ala382Asp	missense_variant	17/17	ENST00000307959.9	NP_004303.2
ARR3	XM_047442105.1	c.1169C>A	p.Ala390Asp	missense_variant	16/16		XP_047298061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARR3	ENST00000307959.9	c.1145C>A	p.Ala382Asp	missense_variant	17/17	1	NM_004312.3	ENSP00000311538.8
PDZD11	ENST00000695560.1	n.*628G>T		non_coding_transcript_exon_variant	8/8			ENSP00000512017.1
PDZD11	ENST00000695560.1	n.*628G>T		3_prime_UTR_variant	8/8			ENSP00000512017.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000187 AC: 2 AN: 1068655 Hom.: 0 Cov.: 30 AF XY: 0.00000288 AC XY: 1 AN XY: 347117

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: 0.00000121

Gnomad4 OTH exome AF: 0.0000222

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

ARR3-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 17, 2024

The ARR3 c.1145C>A variant is predicted to result in the amino acid substitution p.Ala382Asp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. 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	Benign	0.084
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.074
DANN	Benign	0.83
DEOGEN2	Benign	0.086	.;T
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.48	T;T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.059	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.28	.;N
REVEL	Benign	0.012
Sift	Benign	0.20	.;T
Sift4G	Benign	0.54	T;T
Polyphen		0.099	.;B
Vest4		0.18
MutPred		0.085		Loss of helix (P = 0.0167);Loss of helix (P = 0.0167);
MVP		0.28
MPC		0.11
ClinPred		0.11	T
GERP RS		-2.2
Varity_R		0.14
gMVP		0.34

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: rs1486788796; hg19: chrX-69501594;