5-140558664-C-T

Variant names:

• chr5-140558664-C-T
• rs761829691
• NM_133173.3:c.1382G>A

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133173.3. 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
	APBB3	NM_133173.3	MANE Select	c.1382G>A	p.Gly461Glu	missense	Exon 13 of 13	NP_573419.2	O95704-1
	APBB3	NM_006051.4		c.1403G>A	p.Gly468Glu	missense	Exon 13 of 13	NP_006042.3
	APBB3	NM_133172.3		c.1397G>A	p.Gly466Glu	missense	Exon 12 of 12	NP_573418.2	O95704-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APBB3	ENST00000357560.9	TSL:5 MANE Select	c.1382G>A	p.Gly461Glu	missense	Exon 13 of 13	ENSP00000350171.4	O95704-1
	APBB3	ENST00000356738.6	TSL:1	c.1397G>A	p.Gly466Glu	missense	Exon 12 of 12	ENSP00000349177.2	O95704-3
	APBB3	ENST00000412920.7	TSL:1	c.1376G>A	p.Gly459Glu	missense	Exon 12 of 12	ENSP00000402591.3	O95704-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 250646 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111916

Other (OTH) AF: 0.0000497 AC: 3 AN: 60364

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0662318), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.90	L
PhyloP100		2.9
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.14
Sift	Benign	0.098	T
Sift4G	Benign	0.098	T
Polyphen		1.0	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
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

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