Genetic Variant APBB3:p.Cys357Tyr (chr5-140560467-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_133173.3(APBB3):c.1070G>A(p.Cys357Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,760 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C357S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

APBB3
NM_133173.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.96

Publications

0 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: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.921

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APBB3	NM_133173.3 link	c.1070G>A	p.Cys357Tyr	missense_variant	Exon 12 of 13	ENST00000357560.9	NP_573419.2	O95704-1Q59EH2Q96DX9
APBB3	NM_006051.4 link	c.1091G>A	p.Cys364Tyr	missense_variant	Exon 12 of 13		NP_006042.3	O95704-4Q59EH2Q96DX9
APBB3	NM_133172.3 link	c.1085G>A	p.Cys362Tyr	missense_variant	Exon 11 of 12		NP_573418.2	O95704-3Q59EH2Q96DX9
APBB3	NM_133174.3 link	c.1064G>A	p.Cys355Tyr	missense_variant	Exon 11 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.1070G>A	p.Cys357Tyr	missense_variant	Exon 12 of 13	5	NM_133173.3	ENSP00000350171.4		O95704-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461760

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111976

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 24, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1070G>A (p.C357Y) alteration is located in exon 12 (coding exon 12) of the APBB3 gene. This alteration results from a G to A substitution at nucleotide position 1070, causing the cysteine (C) at amino acid position 357 to be replaced by a tyrosine (Y). 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

0.67

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

.;.;T;.

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.89

D;D;D;D

M_CAP

Benign

0.028

MetaRNN

Pathogenic

0.92

D;D;D;D

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.5

.;.;M;.

PhyloP100

5.0

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-8.7

D;D;D;D

REVEL

Uncertain

0.35

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

D;.;.;D

Vest4

0.84

MutPred

0.79

Gain of disorder (P = 0.0834);.;.;.;

MVP

0.87

MPC

1.2

ClinPred

1.0

GERP RS

5.3

Varity_R

0.95

gMVP

0.88

Mutation Taster

=55/45

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over