17-4720588-G-A

Position:

• chr17-4720588-G-A

Variant summary

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

The NM_004313.4(ARRB2):​c.1084G>A​(p.Ala362Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000277 in 1,478,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000067 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: ARRB2 NM_004313.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.15

Genes affected

ARRB2 (HGNC:712): (arrestin beta 2) Members of arrestin/beta-arrestin protein family are thought to participate in agonist-mediated desensitization of G-protein-coupled receptors and cause specific dampening of cellular responses to stimuli such as hormones, neurotransmitters, or sensory signals. Arrestin beta 2, like arrestin beta 1, was shown to inhibit beta-adrenergic receptor function in vitro. It is expressed at high levels in the central nervous system and may play a role in the regulation of synaptic receptors. Besides the brain, a cDNA for arrestin beta 2 was isolated from thyroid gland, and thus it may also be involved in hormone-specific desensitization of TSH receptors. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2012]

ARRB2 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.087445736).
• BS2: High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARRB2	NM_004313.4	c.1084G>A	p.Ala362Thr	missense_variant, splice_region_variant	14/15	ENST00000269260.7	NP_004304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARRB2	ENST00000269260.7	c.1084G>A	p.Ala362Thr	missense_variant, splice_region_variant	14/15	1	NM_004313.4	ENSP00000269260.2

Frequencies

GnomAD3 genomes AF: 0.0000673 AC: 8 AN: 118792 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000992

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000193

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: 0.0000513

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000273 AC: 6 AN: 219768 Hom.: 0 AF XY: 0.0000252 AC XY: 3 AN XY: 119270

Gnomad AFR exome AF: 0.0000651

Gnomad AMR exome AF: 0.0000368

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000393

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000243 AC: 33 AN: 1359988 Hom.: 0 Cov.: 38 AF XY: 0.0000252 AC XY: 17 AN XY: 675310

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000550

Gnomad4 ASJ exome AF: 0.0000886

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000129

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000249

Gnomad4 OTH exome AF: 0.0000179

GnomAD4 genome AF: 0.0000673 AC: 8 AN: 118792 Hom.: 0 Cov.: 28 AF XY: 0.0000532 AC XY: 3 AN XY: 56422

Gnomad4 AFR AF: 0.0000992

Gnomad4 AMR AF: 0.000193

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000513

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000152 Hom.: 0

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2023

The c.1084G>A (p.A362T) alteration is located in exon 14 (coding exon 14) of the ARRB2 gene. This alteration results from a G to A substitution at nucleotide position 1084, causing the alanine (A) at amino acid position 362 to be replaced by a threonine (T). 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	0.064
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	18
DANN	Benign	0.88
DEOGEN2	Benign	0.29	T;T;.;T;.;.;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.69
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.81	T;.;T;.;T;T;T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.087	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.60	N;.;.;.;.;.;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.050	N;.;.;.;.;.;.
REVEL	Benign	0.061
Sift	Benign	0.31	T;.;.;.;.;.;.
Sift4G	Benign	0.48	T;T;T;T;T;T;T
Polyphen		0.086	B;.;P;.;.;.;.
Vest4		0.10
MVP		0.57
MPC		0.81
ClinPred		0.034	T
GERP RS		1.8
Varity_R		0.021
gMVP		0.17

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: rs373325288; hg19: chr17-4623883;