Genetic Variant NM_133173.3:c.1382G>A (chr5-140558664-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_133173.3(APBB3):c.1382G>A(p.Gly461Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,562 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

APBB3
NM_133173.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.88

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APBB3	NM_133173.3 link	c.1382G>A	p.Gly461Glu	missense_variant	Exon 13 of 13	ENST00000357560.9	NP_573419.2	O95704-1Q59EH2Q96DX9
APBB3	NM_006051.4 link	c.1403G>A	p.Gly468Glu	missense_variant	Exon 13 of 13		NP_006042.3	O95704-4Q59EH2Q96DX9
APBB3	NM_133172.3 link	c.1397G>A	p.Gly466Glu	missense_variant	Exon 12 of 12		NP_573418.2	O95704-3Q59EH2Q96DX9
APBB3	NM_133174.3 link	c.1376G>A	p.Gly459Glu	missense_variant	Exon 12 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.1382G>A	p.Gly461Glu	missense_variant	Exon 13 of 13	5	NM_133173.3	ENSP00000350171.4		O95704-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461562

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727100

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000497

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1382G>A (p.G461E) alteration is located in exon 13 (coding exon 13) of the APBB3 gene. This alteration results from a G to A substitution at nucleotide position 1382, causing the glycine (G) at amino acid position 461 to be replaced by a glutamic acid (E). 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

0.12

BayesDel_addAF

Benign

0.0020

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.037

.;.;T;.

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.91

D;D;D;D

M_CAP

Benign

0.022

MetaRNN

Uncertain

0.53

D;D;D;D

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.90

.;.;L;.

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.37

N;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.098

T;T;T;T

Sift4G

Benign

0.098

T;T;T;T

Polyphen

1.0

D;.;.;D

Vest4

0.66

MutPred

0.27

Gain of ubiquitination at K471 (P = 0.0338);.;.;.;

MVP

0.67

MPC

1.0

ClinPred

0.86

GERP RS

5.0

Varity_R

0.11

gMVP

0.42

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over