Genetic Variant APBB3:p.Arg467Leu (chr5-140558646-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_133173.3(APBB3):c.1400G>T(p.Arg467Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R467P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

APBB3
NM_133173.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.04

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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.756

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.1400G>T	p.Arg467Leu	missense	Exon 13 of 13	NP_573419.2	O95704-1
APBB3	NM_006051.4		c.1421G>T	p.Arg474Leu	missense	Exon 13 of 13	NP_006042.3
APBB3	NM_133172.3		c.1415G>T	p.Arg472Leu	missense	Exon 12 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.1400G>T	p.Arg467Leu	missense	Exon 13 of 13	ENSP00000350171.4	O95704-1
APBB3	ENST00000356738.6	TSL:1	c.1415G>T	p.Arg472Leu	missense	Exon 12 of 12	ENSP00000349177.2	O95704-3
APBB3	ENST00000412920.7	TSL:1	c.1394G>T	p.Arg465Leu	missense	Exon 12 of 12	ENSP00000402591.3	O95704-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111998

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.060

MetaRNN

Pathogenic

0.76

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.97

PhyloP100

3.0

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.21

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.82

MutPred

0.51

Loss of MoRF binding (P = 0.0094)

MVP

0.55

MPC

1.0

ClinPred

0.94

GERP RS

5.0

Varity_R

0.25

gMVP

0.50

Mutation Taster

=57/43

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over