X-70269684-A-G

Variant names:

• chrX-70269684-A-G
• rs2085622143
• NM_004312.3:c.31A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004312.3(ARR3):​c.31A>G​(p.Asn11Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000415 in 1,203,976 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: ARR3 NM_004312.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.54
• Publications: 0 publications found

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]

ARR3 Gene-Disease associations (from GenCC):

• myopia 26, X-linked, female-limited

  Inheritance: XL Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23422167).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004312.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARR3	NM_004312.3	MANE Select	c.31A>G	p.Asn11Asp	missense	Exon 3 of 17	NP_004303.2	P36575-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARR3	ENST00000307959.9	TSL:1 MANE Select	c.31A>G	p.Asn11Asp	missense	Exon 3 of 17	ENSP00000311538.8	P36575-1
	ARR3	ENST00000374495.7	TSL:1	c.31A>G	p.Asn11Asp	missense	Exon 3 of 16	ENSP00000363619.3	P36575-2
	ARR3	ENST00000480877.6	TSL:5	c.-171A>G		5_prime_UTR	Exon 3 of 8	ENSP00000425505.1	D6RCT3

Frequencies

GnomAD3 genomes AF: 0.0000270 AC: 3 AN: 111120 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000328

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000192

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1092856 Hom.: 0 Cov.: 31 AF XY: 0.00000279 AC XY: 1 AN XY: 359000

African (AFR) AF: 0.0000379 AC: 1 AN: 26354

American (AMR) AF: 0.00 AC: 0 AN: 34867

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19288

East Asian (EAS) AF: 0.00 AC: 0 AN: 30127

South Asian (SAS) AF: 0.00 AC: 0 AN: 52990

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40237

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 838968

Other (OTH) AF: 0.0000218 AC: 1 AN: 45892

GnomAD4 genome AF: 0.0000270 AC: 3 AN: 111120 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33360

African (AFR) AF: 0.0000328 AC: 1 AN: 30517

American (AMR) AF: 0.000192 AC: 2 AN: 10421

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3539

South Asian (SAS) AF: 0.00 AC: 0 AN: 2592

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6001

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52990

Other (OTH) AF: 0.00 AC: 0 AN: 1500

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		5.5
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.054
Sift	Benign	0.23	T
Sift4G	Benign	0.23	T
Polyphen		0.091	B
Vest4		0.24
MutPred		0.46		Loss of MoRF binding (P = 0.0564)
MVP		0.43
MPC		0.084
ClinPred		0.79	D
GERP RS		4.5
Varity_R		0.40
gMVP		0.81
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2085622143; hg19: chrX-69489534;