X-70269896-A-T

Position:

• chrX-70269896-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004312.3(ARR3):​c.93A>T​(p.Glu31Asp) 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 (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: ARR3 NM_004312.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.09

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09630555).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARR3	NM_004312.3	c.93A>T	p.Glu31Asp	missense_variant	Exon 4 of 17	ENST00000307959.9	NP_004303.2
ARR3	XM_047442105.1	c.93A>T	p.Glu31Asp	missense_variant	Exon 3 of 16		XP_047298061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARR3	ENST00000307959.9	c.93A>T	p.Glu31Asp	missense_variant	Exon 4 of 17	1	NM_004312.3	ENSP00000311538.8
ARR3	ENST00000374495.7	c.93A>T	p.Glu31Asp	missense_variant	Exon 4 of 16	1		ENSP00000363619.3
ARR3	ENST00000480877	c.-61A>T		5_prime_UTR_variant	Exon 4 of 8	5		ENSP00000425505.1
ARR3	ENST00000477379.5	n.312A>T		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2024

The c.93A>T (p.E31D) alteration is located in exon 4 (coding exon 3) of the ARR3 gene. This alteration results from a A to T substitution at nucleotide position 93, causing the glutamic acid (E) at amino acid position 31 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-1.0
CADD	Benign	8.8
DANN	Benign	0.35
DEOGEN2	Benign	0.090	.;.;T
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.83	T;T;T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.096	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.11	N;.;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	1.2	N;.;N
REVEL	Benign	0.057
Sift	Benign	1.0	T;.;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0030	B;.;B
Vest4		0.11
MutPred		0.73		Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);
MVP		0.34
MPC		0.075
ClinPred		0.030	T
GERP RS		2.2
Varity_R		0.079
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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-69489746;