15-29054048-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001353788.2(APBA2):c.164G>A(p.Ser55Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00578 in 1,613,828 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0059 (53 hom.)
• Consequence: APBA2 NM_001353788.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.96

Genes affected

APBA2 (HGNC:579): (amyloid beta precursor protein binding family A member 2) The protein encoded by this gene is a member of the X11 protein family. It is a neuronal adapter protein that interacts with the Alzheimer's disease amyloid precursor protein (APP). It stabilizes APP and inhibits production of proteolytic APP fragments including the A beta peptide that is deposited in the brains of Alzheimer's disease patients. This gene product is believed to be involved in signal transduction processes. It is also regarded as a putative vesicular trafficking protein in the brain that can form a complex with the potential to couple synaptic vesicle exocytosis to neuronal cell adhesion. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0073262453).
• BP6: Variant 15-29054048-G-A is Benign according to our data. Variant chr15-29054048-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 715589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APBA2	NM_001353788.2	c.164G>A	p.Ser55Asn	missense_variant	4/15	ENST00000683413.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APBA2	ENST00000683413.1	c.164G>A	p.Ser55Asn	missense_variant	4/15		NM_001353788.2	P1

Frequencies

GnomAD3 genomes AF: 0.00499 AC: 759 AN: 152168 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00805

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00761

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00527 AC: 1323 AN: 251160 Hom.: 14 AF XY: 0.00549 AC XY: 746 AN XY: 135800

Gnomad AFR exome AF: 0.000925

Gnomad AMR exome AF: 0.00465

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00559

Gnomad FIN exome AF: 0.00360

Gnomad NFE exome AF: 0.00740

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00586 AC: 8562 AN: 1461542 Hom.: 53 Cov.: 32 AF XY: 0.00599 AC XY: 4358 AN XY: 727054

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.00510

Gnomad4 ASJ exome AF: 0.00260

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00606

Gnomad4 FIN exome AF: 0.00446

Gnomad4 NFE exome AF: 0.00644

Gnomad4 OTH exome AF: 0.00532

GnomAD4 genome AF: 0.00498 AC: 759 AN: 152286 Hom.: 5 Cov.: 32 AF XY: 0.00471 AC XY: 351 AN XY: 74464

Gnomad4 AFR AF: 0.000914

Gnomad4 AMR AF: 0.00804

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.00292

Gnomad4 NFE AF: 0.00762

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.00629 Hom.: 2

Bravo AF: 0.00447

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00547 AC: 47

ExAC AF: 0.00586 AC: 711

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00671

EpiControl AF: 0.00622

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	APBA2: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	May 31, 2018	- -

APBA2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 11, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.20	T;T;.;T;T;.;T;T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.0073	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.2	M;M;M;.;M;M;.;.
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.14	N;N;N;D;N;N;N;N
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D
Sift4G	Benign	0.41	T;T;T;D;T;T;D;D
Polyphen		0.99	D;D;.;.;D;.;.;.
Vest4		0.38
MVP		0.70
MPC		0.95
ClinPred		0.042	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.16
gMVP		0.23

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: rs142678624; hg19: chr15-29346251; COSMIC: COSV68794980; COSMIC: COSV68794980;