5-140558664-C-T

Position:

• chr5-140558664-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_133173.3(APBB3):​c.1382G>A​(p.Gly461Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,562 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: APBB3 NM_133173.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.88

Genes affected

APBB3 (HGNC:20708): (amyloid beta precursor protein binding family B member 3) The protein encoded by this gene is a member of the APBB protein family. It is found in the cytoplasm and binds to the intracellular domain of the Alzheimer's disease beta-amyloid precursor protein (APP) as well as to other APP-like proteins. It is thought that the protein encoded by this gene may modulate the internalization of APP. Multiple transcript variants encoding several different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

APBB3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APBB3	NM_133173.3	c.1382G>A	p.Gly461Glu	missense_variant	13/13	ENST00000357560.9	NP_573419.2
APBB3	NM_006051.4	c.1403G>A	p.Gly468Glu	missense_variant	13/13		NP_006042.3
APBB3	NM_133172.3	c.1397G>A	p.Gly466Glu	missense_variant	12/12		NP_573418.2
APBB3	NM_133174.3	c.1376G>A	p.Gly459Glu	missense_variant	12/12		NP_573420.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APBB3	ENST00000357560.9	c.1382G>A	p.Gly461Glu	missense_variant	13/13	5	NM_133173.3	ENSP00000350171.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461562 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727100

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: 0.00

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2023

The c.1382G>A (p.G461E) alteration is located in exon 13 (coding exon 13) of the APBB3 gene. This alteration results from a G to A substitution at nucleotide position 1382, causing the glycine (G) at amino acid position 461 to be replaced by a glutamic acid (E). 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	0.12
BayesDel_addAF	Benign	0.0020	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.037	.;.;T;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.53	D;D;D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.90	.;.;L;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.37	N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.098	T;T;T;T
Sift4G	Benign	0.098	T;T;T;T
Polyphen		1.0	D;.;.;D
Vest4		0.66
MutPred		0.27		Gain of ubiquitination at K471 (P = 0.0338);.;.;.;
MVP		0.67
MPC		1.0
ClinPred		0.86	D
GERP RS		5.0
Varity_R		0.11
gMVP		0.42

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

Other links and lift over

dbSNP: rs761829691; hg19: chr5-139938249; COSMIC: COSV100296210; COSMIC: COSV100296210;