Genetic Variant NM_004886.4:c.1654G>C (chr19-3751191-C-G) – 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.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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E552K) has been classified as Uncertain significance.

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

Publications

0 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, 0.811

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.1654G>C	p.Glu552Gln	missense splice_region	Exon 10 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.1654G>C	p.Glu552Gln	missense splice_region	Exon 10 of 11	ENSP00000315136.2	O96018
APBA3	ENST00000590064.1	TSL:1	n.4029G>C		splice_region non_coding_transcript_exon	Exon 3 of 4
APBA3	ENST00000591678.1	TSL:1	n.541G>C		splice_region non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000638

AC:

AN:

156644

AF XY:

0.0000120

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:

0.0000164

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

African (AFR)

AF:

0.00

AC:

AN:

31858

American (AMR)

AF:

0.00

AC:

AN:

35910

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25160

East Asian (EAS)

AF:

0.00

AC:

AN:

36086

South Asian (SAS)

AF:

0.00

AC:

AN:

79416

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47796

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5064

European-Non Finnish (NFE)

AF:

0.00000185

AC:

AN:

1080296

Other (OTH)

AF:

0.00

AC:

AN:

58032

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.022

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

(source)

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

PhyloP100

5.8

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

Mutation Taster

=35/65

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over