rs140505250

chrX-70280804-C-GchrX-70280804-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004312.3(ARR3):c.1052C>G(p.Pro351Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00177 in 1,209,147 control chromosomes in the GnomAD database, including 1 homozygotes. There are 690 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P351L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., 51 hem., cov: 21)
  • Exomes 𝑓: 0.0018 (1 hom. 639 hem.)
• Consequence: ARR3 NM_004312.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.82

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_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14858988).
• BS2: High Hemizygotes in GnomAd at 51 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARR3	NM_004312.3	c.1052C>G	p.Pro351Arg	missense_variant	15/17	ENST00000307959.9
ARR3	XM_047442105.1	c.1076C>G	p.Pro359Arg	missense_variant	14/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARR3	ENST00000307959.9	c.1052C>G	p.Pro351Arg	missense_variant	15/17	1	NM_004312.3	P1
ARR3	ENST00000374495.7	c.1052C>G	p.Pro351Arg	missense_variant	15/16	1

Frequencies

GnomAD3 genomes AF: 0.00174 AC: 193 AN: 110960 Hom.: 0 Cov.: 21 AF XY: 0.00154 AC XY: 51 AN XY: 33162

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000669

Gnomad ASJ AF: 0.00114

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000388

Gnomad FIN AF: 0.00233

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00314

Gnomad OTH AF: 0.00134

GnomAD3 exomes AF: 0.00158 AC: 290 AN: 183385 Hom.: 0 AF XY: 0.00144 AC XY: 98 AN XY: 67821

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000547

Gnomad ASJ exome AF: 0.00160

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000629

Gnomad FIN exome AF: 0.00181

Gnomad NFE exome AF: 0.00261

Gnomad OTH exome AF: 0.00177

GnomAD4 exome AF: 0.00178 AC: 1953 AN: 1098133 Hom.: 1 Cov.: 32 AF XY: 0.00176 AC XY: 639 AN XY: 363519

Gnomad4 AFR exome AF: 0.0000758

Gnomad4 AMR exome AF: 0.000739

Gnomad4 ASJ exome AF: 0.00150

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000757

Gnomad4 FIN exome AF: 0.00205

Gnomad4 NFE exome AF: 0.00203

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.00174 AC: 193 AN: 111014 Hom.: 0 Cov.: 21 AF XY: 0.00153 AC XY: 51 AN XY: 33226

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000668

Gnomad4 ASJ AF: 0.00114

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000389

Gnomad4 FIN AF: 0.00233

Gnomad4 NFE AF: 0.00314

Gnomad4 OTH AF: 0.00132

Alfa AF: 0.00288 Hom.: 15

Bravo AF: 0.00134

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00208 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00253 AC: 17

ExAC AF: 0.00175 AC: 212

EpiCase AF: 0.00218

EpiControl AF: 0.00243

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Pathogenic	0.17
Cadd	Uncertain	24
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.70	T;T;T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Pathogenic	3.2	M;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-7.6	D;.;D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.87
MVP		0.84
MPC		0.44
ClinPred		0.14	T
GERP RS		4.8
Varity_R		0.94
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs140505250; hg19: chrX-69500654;