Variant 11-75267689-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_004041.5(ARRB1):c.1108A>T(p.Thr370Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000436 in 1,466,900 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

ARRB1
NM_004041.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.631

Variant links:

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]

ARRB1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019470453).

BS2

High AC in GnomAd4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARRB1	NM_004041.5 linkuse as main transcript	c.1108A>T	p.Thr370Ser	missense_variant	15/16	ENST00000420843.7	NP_004032.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARRB1	ENST00000420843.7 linkuse as main transcript	c.1108A>T	p.Thr370Ser	missense_variant	15/16	1	NM_004041.5	ENSP00000409581	P1	P49407-1
ARRB1	ENST00000360025.7 linkuse as main transcript	c.1084A>T	p.Thr362Ser	missense_variant	14/15	1		ENSP00000353124		P49407-2
ARRB1	ENST00000532447.5 linkuse as main transcript	c.542+1200A>T		intron_variant		5		ENSP00000436530

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

144834

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000323

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000477

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

GnomAD3 exomes

AF:

0.0000519

AC:

AN:

250472

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135504

show subpopulations

Gnomad AFR exome

AF:

0.000619

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.0000333

AC:

AN:

1321918

Hom.:

Cov.:

AF XY:

0.0000274

AC XY:

AN XY:

657460

show subpopulations

Gnomad4 AFR exome

AF:

0.00122

Gnomad4 AMR exome

AF:

0.0000487

Gnomad4 ASJ exome

AF:

0.0000942

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000585

GnomAD4 genome

AF:

0.000138

AC:

AN:

144982

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

70594

show subpopulations

Gnomad4 AFR

AF:

0.000322

Gnomad4 AMR

AF:

0.000476

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000451

Hom.:

Bravo

AF:

0.000227

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 14, 2023

The c.1108A>T (p.T370S) alteration is located in exon 15 (coding exon 15) of the ARRB1 gene. This alteration results from a A to T substitution at nucleotide position 1108, causing the threonine (T) at amino acid position 370 to be replaced by a serine (S). 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

0.070

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.70

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.19

T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.68

T;T

M_CAP

Benign

0.0063

MetaRNN

Benign

0.019

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.69

N;.

MutationTaster

Benign

0.98

N;N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.24

N;N

REVEL

Benign

0.025

Sift

Benign

0.67

T;T

Sift4G

Benign

0.76

T;T

Polyphen

0.0

B;B

Vest4

0.32

MVP

0.21

MPC

0.64

ClinPred

0.0087

GERP RS

-1.3

Varity_R

0.021

gMVP

0.11

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over