chr11-75283348-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_004041.5(ARRB1):​c.293C>A​(p.Thr98Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ARRB1
NM_004041.5 missense

Scores

10
5
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.07
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.851

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ARRB1NM_004041.5 linkuse as main transcriptc.293C>A p.Thr98Lys missense_variant 5/16 ENST00000420843.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ARRB1ENST00000420843.7 linkuse as main transcriptc.293C>A p.Thr98Lys missense_variant 5/161 NM_004041.5 P1P49407-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461794
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727208
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

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 submitterclinical testingAmbry GeneticsApr 15, 2024The c.293C>A (p.T98K) alteration is located in exon 5 (coding exon 5) of the ARRB1 gene. This alteration results from a C to A substitution at nucleotide position 293, causing the threonine (T) at amino acid position 98 to be replaced by a lysine (K). 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
Pathogenic
0.98
BayesDel_addAF
Uncertain
0.095
D
BayesDel_noAF
Benign
-0.10
CADD
Pathogenic
31
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.54
D;.;T
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
D;D;D
M_CAP
Benign
0.062
D
MetaRNN
Pathogenic
0.85
D;D;D
MetaSVM
Benign
-0.48
T
MutationAssessor
Pathogenic
3.5
H;H;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.73
T
PROVEAN
Pathogenic
-5.3
D;D;D
REVEL
Uncertain
0.46
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0010
D;D;.
Polyphen
1.0
D;D;.
Vest4
0.81
MutPred
0.70
Loss of ubiquitination at K95 (P = 0.0175);Loss of ubiquitination at K95 (P = 0.0175);.;
MVP
0.69
MPC
1.9
ClinPred
1.0
D
GERP RS
4.3
Varity_R
0.91
gMVP
0.82

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-74994392; API