Genetic Variant APBB3:p.Cys231Arg (chr5-140561643-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_133173.3(APBB3):c.691T>C(p.Cys231Arg) variant causes a missense change. The variant allele was found at a frequency of 0.864 in 1,614,146 control chromosomes in the GnomAD database, including 602,784 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.88 ( 59239 hom., cov: 34)

Exomes 𝑓: 0.86 ( 543545 hom. )

Consequence

APBB3
NM_133173.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.74

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 made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.1325994E-6).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.933 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APBB3	NM_133173.3 link	c.691T>C	p.Cys231Arg	missense_variant	Exon 8 of 13	ENST00000357560.9	NP_573419.2	O95704-1Q59EH2Q96DX9
APBB3	NM_006051.4 link	c.712T>C	p.Cys238Arg	missense_variant	Exon 8 of 13		NP_006042.3	O95704-4Q59EH2Q96DX9
APBB3	NM_133172.3 link	c.706T>C	p.Cys236Arg	missense_variant	Exon 7 of 12		NP_573418.2	O95704-3Q59EH2Q96DX9
APBB3	NM_133174.3 link	c.685T>C	p.Cys229Arg	missense_variant	Exon 7 of 12		NP_573420.2	O95704-2Q59EH2Q96DX9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APBB3	ENST00000357560.9 link	c.691T>C	p.Cys231Arg	missense_variant	Exon 8 of 13	5	NM_133173.3	ENSP00000350171.4		O95704-1

Frequencies

GnomAD3 genomes

AF:

0.881

AC:

133997

AN:

152178

Hom.:

59188

Cov.:

show subpopulations

Gnomad AFR

AF:

0.941

Gnomad AMI

AF:

0.908

Gnomad AMR

AF:

0.867

Gnomad ASJ

AF:

0.832

Gnomad EAS

AF:

0.894

Gnomad SAS

AF:

0.904

Gnomad FIN

AF:

0.798

Gnomad MID

AF:

0.968

Gnomad NFE

AF:

0.859

Gnomad OTH

AF:

0.886

GnomAD3 exomes

AF:

0.866

AC:

217621

AN:

251432

Hom.:

94433

AF XY:

0.868

AC XY:

117984

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.939

Gnomad AMR exome

AF:

0.841

Gnomad ASJ exome

AF:

0.839

Gnomad EAS exome

AF:

0.888

Gnomad SAS exome

AF:

0.914

Gnomad FIN exome

AF:

0.796

Gnomad NFE exome

AF:

0.861

Gnomad OTH exome

AF:

0.863

GnomAD4 exome

AF:

0.862

AC:

1259833

AN:

1461850

Hom.:

543545

Cov.:

AF XY:

0.864

AC XY:

628090

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.940

Gnomad4 AMR exome

AF:

0.844

Gnomad4 ASJ exome

AF:

0.833

Gnomad4 EAS exome

AF:

0.888

Gnomad4 SAS exome

AF:

0.912

Gnomad4 FIN exome

AF:

0.794

Gnomad4 NFE exome

AF:

0.858

Gnomad4 OTH exome

AF:

0.873

GnomAD4 genome

AF:

0.881

AC:

134106

AN:

152296

Hom.:

59239

Cov.:

AF XY:

0.877

AC XY:

65296

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.941

Gnomad4 AMR

AF:

0.867

Gnomad4 ASJ

AF:

0.832

Gnomad4 EAS

AF:

0.893

Gnomad4 SAS

AF:

0.904

Gnomad4 FIN

AF:

0.798

Gnomad4 NFE

AF:

0.859

Gnomad4 OTH

AF:

0.888

Alfa

AF:

0.867

Hom.:

143371

Bravo

AF:

0.889

TwinsUK

AF:

0.865

AC:

3207

ALSPAC

AF:

0.861

AC:

3319

ESP6500AA

AF:

0.939

AC:

4137

ESP6500EA

AF:

0.865

AC:

7436

ExAC

AF:

0.869

AC:

105541

Asia WGS

AF:

0.909

AC:

3164

AN:

3478

EpiCase

AF:

0.872

EpiControl

AF:

0.873

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.036

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.020

T;.;.;T;.;T

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.37

T;T;T;T;T;T

MetaRNN

Benign

0.0000011

T;T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-2.4

.;.;.;N;.;.

PrimateAI

Benign

0.34

PROVEAN

Benign

7.2

N;N;N;N;N;N

REVEL

Benign

0.13

Sift

Benign

1.0

T;T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T;T

Polyphen

0.0

.;B;.;.;B;B

Vest4

0.12

MPC

0.44

ClinPred

0.013

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.16

gMVP

0.62

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

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over