chr5-140560344-C-T

Position:

• chr5-140560344-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_133173.3(APBB3):​c.1193G>A​(p.Gly398Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000402 in 1,613,520 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00046 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00040 (5 hom.)
• Consequence: APBB3 NM_133173.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0780

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04084274).
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APBB3	NM_133173.3	c.1193G>A	p.Gly398Glu	missense_variant	12/13	ENST00000357560.9	NP_573419.2
APBB3	NM_006051.4	c.1214G>A	p.Gly405Glu	missense_variant	12/13		NP_006042.3
APBB3	NM_133172.3	c.1208G>A	p.Gly403Glu	missense_variant	11/12		NP_573418.2
APBB3	NM_133174.3	c.1187G>A	p.Gly396Glu	missense_variant	11/12		NP_573420.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APBB3	ENST00000357560.9	c.1193G>A	p.Gly398Glu	missense_variant	12/13	5	NM_133173.3	ENSP00000350171.4

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152142 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000486 AC: 122 AN: 251278 Hom.: 2 AF XY: 0.000611 AC XY: 83 AN XY: 135838

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00114

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000607

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000396 AC: 578 AN: 1461266 Hom.: 5 Cov.: 32 AF XY: 0.000431 AC XY: 313 AN XY: 726978

Gnomad4 AFR exome AF: 0.000182

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00115

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000334

Gnomad4 OTH exome AF: 0.000498

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152254 Hom.: 1 Cov.: 33 AF XY: 0.000551 AC XY: 41 AN XY: 74464

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000676

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000401 Hom.: 0

Bravo AF: 0.000438

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000560 AC: 68

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00124

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

Jul 14, 2021

The c.1193G>A (p.G398E) alteration is located in exon 12 (coding exon 12) of the APBB3 gene. This alteration results from a G to A substitution at nucleotide position 1193, causing the glycine (G) at amino acid position 398 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	0.096
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.070	.;.;T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.034
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.90	D;T;D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.041	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	.;.;L;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.52	N;N;N;N
REVEL	Benign	0.057
Sift	Benign	0.087	T;T;T;T
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.47	P;.;.;P
Vest4		0.38
MVP		0.59
MPC		0.45
ClinPred		0.016	T
GERP RS		4.6
Varity_R		0.096
gMVP		0.75

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: rs148009989; hg19: chr5-139939929;