Variant 11-6395823-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001164.5(APBB1):c.1928C>T(p.Ala643Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

APBB1
NM_001164.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.00

Variant links:

Genes affected

APBB1 (HGNC:581): (amyloid beta precursor protein binding family B member 1) The protein encoded by this gene is a member of the Fe65 protein family. It is an adaptor protein localized in the nucleus. It interacts with the Alzheimer's disease amyloid precursor protein (APP), transcription factor CP2/LSF/LBP1 and the low-density lipoprotein receptor-related protein. APP functions as a cytosolic anchoring site that can prevent the gene product's nuclear translocation. This encoded protein could play an important role in the pathogenesis of Alzheimer's disease. It is thought to regulate transcription. Also it is observed to block cell cycle progression by downregulating thymidylate synthase expression. Multiple alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Mar 2012]

APBB1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.933

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APBB1	NM_001164.5 linkuse as main transcript	c.1928C>T	p.Ala643Val	missense_variant	14/15	ENST00000609360.6	NP_001155.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APBB1	ENST00000609360.6 linkuse as main transcript	c.1928C>T	p.Ala643Val	missense_variant	14/15	5	NM_001164.5	ENSP00000477213	A1	O00213-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

250662

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135520

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461834

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000895

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2023

The c.1928C>T (p.A643V) alteration is located in exon 14 (coding exon 13) of the APBB1 gene. This alteration results from a C to T substitution at nucleotide position 1928, causing the alanine (A) at amino acid position 643 to be replaced by a valine (V). 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

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.031

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.32

T;T;T;T;.;.;.;T;.;.;.;.;.;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;.;D;D;D;.;.;D;D;.;D;D;D;D

M_CAP

Benign

0.073

MetaRNN

Pathogenic

0.93

D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.42

MutationAssessor

Uncertain

2.9

.;.;.;.;.;.;.;M;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-3.2

.;.;.;D;.;.;D;.;D;.;.;.;.;D

REVEL

Uncertain

0.61

Sift

Uncertain

0.0010

.;.;.;D;.;.;D;.;D;.;.;.;.;D

Sift4G

Uncertain

0.0030

D;D;D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0

.;.;.;.;.;.;D;D;D;.;.;.;.;.

Vest4

0.83

MutPred

0.86

.;.;.;Loss of glycosylation at P641 (P = 0.0852);.;.;.;Loss of glycosylation at P641 (P = 0.0852);.;.;.;.;.;.;

MVP

0.65

MPC

1.6

ClinPred

0.93

GERP RS

4.6

Varity_R

0.76

gMVP

0.98

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