Genetic Variant APBA3:p.Glu495Lys (chr19-3751466-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_004886.4(APBA3):c.1483G>A(p.Glu495Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000217 in 1,555,236 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00021 ( 1 hom. )

Consequence

APBA3
NM_004886.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.80

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3024522).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APBA3	NM_004886.4 link	c.1483G>A	p.Glu495Lys	missense_variant	Exon 9 of 11	ENST00000316757.4	NP_004877.1	O96018
APBA3	XM_006722950.5 link	c.1483G>A	p.Glu495Lys	missense_variant	Exon 9 of 10		XP_006723013.1
APBA3	XM_006722951.4 link	c.757G>A	p.Glu253Lys	missense_variant	Exon 7 of 8		XP_006723014.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APBA3	ENST00000316757.4 link	c.1483G>A	p.Glu495Lys	missense_variant	Exon 9 of 11	1	NM_004886.4	ENSP00000315136.2		O96018

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

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:

0.000397

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.000134

AC:

AN:

164306

Hom.:

AF XY:

0.000124

AC XY:

AN XY:

88658

show subpopulations

Gnomad AFR exome

AF:

0.000204

Gnomad AMR exome

AF:

0.000121

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000423

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000219

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.000215

AC:

301

AN:

1403156

Hom.:

Cov.:

AF XY:

0.000231

AC XY:

160

AN XY:

694066

show subpopulations

Gnomad4 AFR exome

AF:

0.000407

Gnomad4 AMR exome

AF:

0.000168

Gnomad4 ASJ exome

AF:

0.0000398

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000375

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000233

Gnomad4 OTH exome

AF:

0.000189

GnomAD4 genome

AF:

0.000243

AC:

AN:

152080

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.000958

Alfa

AF:

0.000192

Hom.:

Bravo

AF:

0.000230

ESP6500AA

AF:

0.000460

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.000203

AC:

Asia WGS

AF:

0.000289

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

Nov 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1483G>A (p.E495K) alteration is located in exon 9 (coding exon 8) of the APBA3 gene. This alteration results from a G to A substitution at nucleotide position 1483, causing the glutamic acid (E) at amino acid position 495 to be replaced by a lysine (K). 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

0.20

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.47

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

Eigen

Benign

0.024

Eigen_PC

Benign

0.052

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.036

MetaRNN

Benign

0.30

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.5

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-0.54

REVEL

Benign

0.090

Sift

Benign

0.34

Sift4G

Uncertain

0.028

Polyphen

0.73

Vest4

0.60

MVP

0.47

MPC

0.14

ClinPred

0.047

GERP RS

4.7

Varity_R

0.15

gMVP

0.52

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