Genetic Variant APBA3:p.Val478Phe (chr19-3751517-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_004886.4(APBA3):c.1432G>T(p.Val478Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000145 in 1,588,702 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. V478I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

APBA3
NM_004886.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.13

Publications

2 publications found

Variant links:

Genes affected

APBA3 (HGNC:580): (amyloid beta precursor protein binding family A member 3) The protein encoded by this gene is a member of the X11 protein family. It is an adapter protein that interacts with the Alzheimer's disease amyloid precursor protein. This gene product is believed to be involved in signal transduction processes. This gene is a candidate gene for Alzheimer's disease. [provided by RefSeq, Jul 2008]

APBA3 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, 0.809

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004886.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APBA3	NM_004886.4	MANE Select	c.1432G>T	p.Val478Phe	missense	Exon 9 of 11	NP_004877.1	O96018

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APBA3	ENST00000316757.4	TSL:1 MANE Select	c.1432G>T	p.Val478Phe	missense	Exon 9 of 11	ENSP00000315136.2	O96018
APBA3	ENST00000590064.1	TSL:1	n.3703G>T		non_coding_transcript_exon	Exon 3 of 4
APBA3	ENST00000591678.1	TSL:1	n.215G>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000144

AC:

AN:

209018

AF XY:

0.00000880

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000217

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000146

AC:

AN:

1436508

Hom.:

Cov.:

AF XY:

0.0000168

AC XY:

AN XY:

713078

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32800

American (AMR)

AF:

0.00

AC:

AN:

41470

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25660

East Asian (EAS)

AF:

0.00

AC:

AN:

38496

South Asian (SAS)

AF:

0.0000120

AC:

AN:

83008

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48716

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4202

European-Non Finnish (NFE)

AF:

0.0000172

AC:

AN:

1102818

Other (OTH)

AF:

0.0000169

AC:

AN:

59338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

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:

0.0000131

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41450

American (AMR)

AF:

0.000131

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.0000166

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.81

MetaSVM

Benign

-0.69

MutationAssessor

Pathogenic

3.7

PhyloP100

3.1

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-4.6

REVEL

Uncertain

0.30

Sift

Uncertain

0.0050

Sift4G

Pathogenic

0.0010

Polyphen

0.99

Vest4

0.70

MutPred

0.51

Loss of stability (P = 0.1126)

MVP

0.65

MPC

0.37

ClinPred

0.90

GERP RS

2.5

Varity_R

0.22

gMVP

0.60

Mutation Taster

=53/47

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