dbSNP rs368800499: APBA3:p.Glu552Gln (chr19-3751191-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_004886.4(APBA3):c.1654G>C(p.Glu552Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000143 in 1,399,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

APBA3
NM_004886.4 missense, splice_region

Scores

Splicing: ADA: 0.9123

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.82

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 made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.811

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APBA3	NM_004886.4 link	c.1654G>C	p.Glu552Gln	missense_variant, splice_region_variant	Exon 10 of 11	ENST00000316757.4	NP_004877.1	O96018
APBA3	XM_006722950.5 link	c.1758G>C	p.Ala586Ala	splice_region_variant, synonymous_variant	Exon 9 of 10		XP_006723013.1
APBA3	XM_006722951.4 link	c.1032G>C	p.Ala344Ala	splice_region_variant, synonymous_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.1654G>C	p.Glu552Gln	missense_variant, splice_region_variant	Exon 10 of 11	1	NM_004886.4	ENSP00000315136.2		O96018

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000638

AC:

AN:

156644

Hom.:

AF XY:

0.0000120

AC XY:

AN XY:

82992

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000164

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1399618

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

690694

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000185

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.022

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.83

M_CAP

Benign

0.042

MetaRNN

Pathogenic

0.81

MetaSVM

Benign

-0.64

MutationAssessor

Uncertain

2.3

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.24

Sift

Benign

0.032

Sift4G

Uncertain

0.040

Polyphen

0.98

Vest4

0.72

MutPred

0.49

Gain of helix (P = 0.132);

MVP

0.43

MPC

0.33

ClinPred

0.94

GERP RS

4.7

Varity_R

0.32

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.91

dbscSNV1_RF

Pathogenic

0.82

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over