15-29054039-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001353788.2(APBA2):c.155G>A(p.Arg52Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0168 in 1,613,814 control chromosomes in the GnomAD database, including 290 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (16 hom., cov: 32)
  • Exomes 𝑓: 0.017 (274 hom.)
• Consequence: APBA2 NM_001353788.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.24

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037463903).
• BP6: Variant 15-29054039-G-A is Benign according to our data. Variant chr15-29054039-G-A is described in ClinVar as [Benign]. Clinvar id is 3037758.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0125 (1898/152268) while in subpopulation NFE AF= 0.019 (1291/68024). AF 95% confidence interval is 0.0181. There are 16 homozygotes in gnomad4. There are 925 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 16 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APBA2	NM_001353788.2	c.155G>A	p.Arg52Gln	missense_variant	4/15	ENST00000683413.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APBA2	ENST00000683413.1	c.155G>A	p.Arg52Gln	missense_variant	4/15		NM_001353788.2	P1

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1897 AN: 152150 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00401

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00929

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00995

Gnomad FIN AF: 0.0172

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0190

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.0135 AC: 3381 AN: 251142 Hom.: 37 AF XY: 0.0140 AC XY: 1905 AN XY: 135804

Gnomad AFR exome AF: 0.00444

Gnomad AMR exome AF: 0.00758

Gnomad ASJ exome AF: 0.00903

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00817

Gnomad FIN exome AF: 0.0170

Gnomad NFE exome AF: 0.0199

Gnomad OTH exome AF: 0.0132

GnomAD4 exome AF: 0.0173 AC: 25265 AN: 1461546 Hom.: 274 Cov.: 32 AF XY: 0.0172 AC XY: 12481 AN XY: 727046

Gnomad4 AFR exome AF: 0.00296

Gnomad4 AMR exome AF: 0.00771

Gnomad4 ASJ exome AF: 0.00945

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00827

Gnomad4 FIN exome AF: 0.0172

Gnomad4 NFE exome AF: 0.0197

Gnomad4 OTH exome AF: 0.0159

GnomAD4 genome AF: 0.0125 AC: 1898 AN: 152268 Hom.: 16 Cov.: 32 AF XY: 0.0124 AC XY: 925 AN XY: 74444

Gnomad4 AFR AF: 0.00402

Gnomad4 AMR AF: 0.00928

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00996

Gnomad4 FIN AF: 0.0172

Gnomad4 NFE AF: 0.0190

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.0135 Hom.: 14

Bravo AF: 0.0112

TwinsUK AF: 0.0232 AC: 86

ALSPAC AF: 0.0182 AC: 70

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0184 AC: 158

ExAC AF: 0.0144 AC: 1746

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0175

EpiControl AF: 0.0194

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

APBA2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 26, 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	0.069
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.21	T;T;.;T;T;.;T;T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.50	D
MetaRNN	Benign	0.0037	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.2	M;M;M;.;M;M;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.19	N;N;N;D;N;N;D;N
Sift	Benign	0.042	D;D;D;T;D;D;T;T
Sift4G	Benign	0.25	T;T;T;T;T;T;T;T
Polyphen		0.0010	B;B;.;.;B;.;.;.
Vest4		0.042
MPC		0.47
ClinPred		0.015	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.033
gMVP		0.34

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: rs117098828; hg19: chr15-29346242; COSMIC: COSV99065425; COSMIC: COSV99065425;