15-29054403-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001353788.2(APBA2):c.519C>T(p.Ser173=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00157 in 1,614,100 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0086 (26 hom., cov: 32)
  • Exomes 𝑓: 0.00084 (13 hom.)
• Consequence: APBA2 NM_001353788.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.56

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 15-29054403-C-T is Benign according to our data. Variant chr15-29054403-C-T is described in ClinVar as [Benign]. Clinvar id is 787114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.56 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0086 (1310/152284) while in subpopulation AFR AF= 0.0304 (1263/41570). AF 95% confidence interval is 0.029. There are 26 homozygotes in gnomad4. There are 594 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 26 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APBA2	NM_001353788.2	c.519C>T	p.Ser173=	synonymous_variant	4/15	ENST00000683413.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APBA2	ENST00000683413.1	c.519C>T	p.Ser173=	synonymous_variant	4/15		NM_001353788.2	P1

Frequencies

GnomAD3 genomes AF: 0.00858 AC: 1306 AN: 152166 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.0304

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00193 AC: 485 AN: 250680 Hom.: 5 AF XY: 0.00132 AC XY: 179 AN XY: 135720

Gnomad AFR exome AF: 0.0281

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000839 AC: 1226 AN: 1461816 Hom.: 13 Cov.: 33 AF XY: 0.000677 AC XY: 492 AN XY: 727204

Gnomad4 AFR exome AF: 0.0309

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000387

Gnomad4 OTH exome AF: 0.00149

GnomAD4 genome AF: 0.00860 AC: 1310 AN: 152284 Hom.: 26 Cov.: 32 AF XY: 0.00798 AC XY: 594 AN XY: 74464

Gnomad4 AFR AF: 0.0304

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00259 Hom.: 4

Bravo AF: 0.00965

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

APBA2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 24, 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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
Cadd	Benign	0.12
Dann	Benign	0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs16955009; hg19: chr15-29346606;