Genetic Variant APBB3:p.Arg323Gln (chr5-140560703-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_133173.3(APBB3):c.968G>A(p.Arg323Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000644 in 1,614,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R323W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

APBB3
NM_133173.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.02

Publications

1 publications found

Variant links:

Genes affected

APBB3 (HGNC:20708): (amyloid beta precursor protein binding family B member 3) The protein encoded by this gene is a member of the APBB protein family. It is found in the cytoplasm and binds to the intracellular domain of the Alzheimer's disease beta-amyloid precursor protein (APP) as well as to other APP-like proteins. It is thought that the protein encoded by this gene may modulate the internalization of APP. Multiple transcript variants encoding several different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

APBB3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012507737).

BP6

Variant 5-140560703-C-T is Benign according to our data. Variant chr5-140560703-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2364526.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133173.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APBB3	NM_133173.3	MANE Select	c.968G>A	p.Arg323Gln	missense	Exon 11 of 13	NP_573419.2	O95704-1
APBB3	NM_006051.4		c.989G>A	p.Arg330Gln	missense	Exon 11 of 13	NP_006042.3
APBB3	NM_133172.3		c.983G>A	p.Arg328Gln	missense	Exon 10 of 12	NP_573418.2	O95704-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APBB3	ENST00000357560.9	TSL:5 MANE Select	c.968G>A	p.Arg323Gln	missense	Exon 11 of 13	ENSP00000350171.4	O95704-1
APBB3	ENST00000356738.6	TSL:1	c.983G>A	p.Arg328Gln	missense	Exon 10 of 12	ENSP00000349177.2	O95704-3
APBB3	ENST00000412920.7	TSL:1	c.962G>A	p.Arg321Gln	missense	Exon 10 of 12	ENSP00000402591.3	O95704-2

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000107

AC:

AN:

251362

AF XY:

0.000110

show subpopulations

Gnomad AFR exome

AF:

0.00111

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:

0.0000616

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000397

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000399

AC XY:

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.000956

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

1112002

Other (OTH)

AF:

0.0000331

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000302

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00103

AC:

AN:

41562

American (AMR)

AF:

0.00

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000141

Hom.:

Bravo

AF:

0.000329

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000123

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.58

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.073

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.83

M_CAP

Benign

0.0084

MetaRNN

Benign

0.013

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PhyloP100

-1.0

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.1

REVEL

Benign

0.042

Sift

Benign

0.25

Sift4G

Benign

0.13

Polyphen

0.0080

Vest4

0.044

MVP

0.37

MPC

0.29

ClinPred

0.012

GERP RS

-5.3

Varity_R

0.10

gMVP

0.42

Mutation Taster

=75/25

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over