Genetic Variant APBA3:p.Cys376Gly (chr19-3752876-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004886.4(APBA3):c.1126T>G(p.Cys376Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00755 in 1,613,188 control chromosomes in the GnomAD database, including 740 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.038 ( 394 hom., cov: 34)

Exomes 𝑓: 0.0044 ( 346 hom. )

Consequence

APBA3
NM_004886.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.967

Publications

35 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037506819).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APBA3	NM_004886.4 link	c.1126T>G	p.Cys376Gly	missense_variant	Exon 7 of 11	ENST00000316757.4	NP_004877.1	O96018
APBA3	XM_006722950.5 link	c.1126T>G	p.Cys376Gly	missense_variant	Exon 7 of 10		XP_006723013.1
APBA3	XM_006722951.4 link	c.400T>G	p.Cys134Gly	missense_variant	Exon 5 of 8		XP_006723014.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
APBA3	ENST00000316757.4 link	c.1126T>G	p.Cys376Gly	missense_variant	Exon 7 of 11	1	NM_004886.4	ENSP00000315136.2	O96018
APBA3	ENST00000590064.1 link	n.3397T>G		non_coding_transcript_exon_variant	Exon 1 of 4	1
APBA3	ENST00000588984.5 link	n.970T>G		non_coding_transcript_exon_variant	Exon 4 of 8	2
APBA3	ENST00000592826.1 link	n.400T>G		non_coding_transcript_exon_variant	Exon 3 of 4	2

Frequencies

GnomAD3 genomes

AF:

0.0378

AC:

5748

AN:

152030

Hom.:

390

Cov.:

show subpopulations

Gnomad AFR

AF:

0.129

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0168

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.000853

Gnomad OTH

AF:

0.0283

GnomAD2 exomes

AF:

0.0102

AC:

2556

AN:

249796

AF XY:

0.00756

show subpopulations

Gnomad AFR exome

AF:

0.133

Gnomad AMR exome

AF:

0.00724

Gnomad ASJ exome

AF:

0.00150

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000834

Gnomad OTH exome

AF:

0.00443

GnomAD4 exome

AF:

0.00439

AC:

6414

AN:

1461040

Hom.:

346

Cov.:

AF XY:

0.00389

AC XY:

2825

AN XY:

726858

show subpopulations

African (AFR)

AF:

0.140

AC:

4689

AN:

33470

American (AMR)

AF:

0.00785

AC:

351

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00241

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.000916

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000189

AC:

AN:

52772

Middle Eastern (MID)

AF:

0.0101

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000522

AC:

580

AN:

1111882

Other (OTH)

AF:

0.00982

AC:

593

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

359

718

1078

1437

1796

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

158

316

474

632

790

<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:

0.0379

AC:

5768

AN:

152148

Hom.:

394

Cov.:

AF XY:

0.0354

AC XY:

2636

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.130

AC:

5378

AN:

41524

American (AMR)

AF:

0.0167

AC:

256

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.000622

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000854

AC:

AN:

67952

Other (OTH)

AF:

0.0280

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

263

527

790

1054

1317

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000179

Hom.:

51411

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ExAC

AF:

0.0123

AC:

1493

EpiCase

AF:

0.00115

EpiControl

AF:

0.00136

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.043

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.81

CADD

Benign

(source)

DANN

Benign

0.45

DEOGEN2

Benign

0.059

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.069

LIST_S2

Benign

0.12

MetaRNN

Benign

0.0038

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-2.2

PhyloP100

0.97

PrimateAI

Benign

0.36

PROVEAN

Benign

1.5

REVEL

Benign

0.039

Sift

Benign

0.48

Sift4G

Benign

0.21

Polyphen

0.0

Vest4

0.020

MPC

0.058

ClinPred

0.0016

GERP RS

1.8

Varity_R

0.028

gMVP

0.62

Mutation Taster

=98/2

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over