11-75274201-C-T

Variant names:

• chr11-75274201-C-T
• rs766062331
• NM_004041.5:c.787G>A

Variant summary

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

The NM_004041.5(ARRB1):​c.787G>A​(p.Ala263Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ARRB1 NM_004041.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.43
• Publications: 2 publications found

Genes affected

ARRB1 (HGNC:711): (arrestin beta 1) 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 1 is a cytosolic protein and acts as a cofactor in the beta-adrenergic receptor kinase (BARK) mediated desensitization of beta-adrenergic receptors. Besides the central nervous system, it is expressed at high levels in peripheral blood leukocytes, and thus the BARK/beta-arrestin system is believed to play a major role in regulating receptor-mediated immune functions. Alternatively spliced transcripts encoding different isoforms of arrestin beta 1 have been described. [provided by RefSeq, Jan 2011]

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=0.24335691).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004041.5. 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
	ARRB1	NM_004041.5	MANE Select	c.787G>A	p.Ala263Thr	missense	Exon 11 of 16	NP_004032.2
	ARRB1	NM_020251.4		c.787G>A	p.Ala263Thr	missense	Exon 11 of 15	NP_064647.1	P49407-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARRB1	ENST00000420843.7	TSL:1 MANE Select	c.787G>A	p.Ala263Thr	missense	Exon 11 of 16	ENSP00000409581.2	P49407-1
	ARRB1	ENST00000360025.7	TSL:1	c.787G>A	p.Ala263Thr	missense	Exon 11 of 15	ENSP00000353124.3	P49407-2
	ARRB1	ENST00000952726.1		c.787G>A	p.Ala263Thr	missense	Exon 11 of 16	ENSP00000622785.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251044 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461800 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727196

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111952

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.4
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.033
Sift	Benign	0.24	T
Sift4G	Benign	0.59	T
Polyphen		0.010	B
Vest4		0.37
MutPred		0.32		Gain of phosphorylation at A263 (P = 0.0211)
MVP		0.36
MPC		0.71
ClinPred		0.47	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.48
Mutation Taster		=69/31	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: rs766062331; hg19: chr11-74985245; COSMIC: COSV100758186;