rs8102086

Positions:

• chr19-3752876-A-C
• chr19-3752876-A-G
• chr19-3752876-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004886.4(APBA3):​c.1126T>G​(p.Cys376Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00755 in 1,613,188 control chromosomes in the GnomAD database, including 740 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C376R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.038 (394 hom., cov: 34)
  • Exomes 𝑓: 0.0044 (346 hom.)
• Consequence: APBA3 NM_004886.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.967

Genes affected

APBA3 (HGNC:580): (amyloid beta precursor protein binding family A member 3) The protein encoded by this gene is a member of the X11 protein family. It is an adapter protein that interacts with the Alzheimer's disease amyloid precursor protein. This gene product is believed to be involved in signal transduction processes. This gene is a candidate gene for Alzheimer's disease. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037506819).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APBA3	NM_004886.4	c.1126T>G	p.Cys376Gly	missense_variant	7/11	ENST00000316757.4
APBA3	XM_006722950.5	c.1126T>G	p.Cys376Gly	missense_variant	7/10
APBA3	XM_006722951.4	c.400T>G	p.Cys134Gly	missense_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APBA3	ENST00000316757.4	c.1126T>G	p.Cys376Gly	missense_variant	7/11	1	NM_004886.4	P1
APBA3	ENST00000590064.1	n.3397T>G		non_coding_transcript_exon_variant	1/4	1
APBA3	ENST00000588984.5	n.970T>G		non_coding_transcript_exon_variant	4/8	2
APBA3	ENST00000592826.1	n.400T>G		non_coding_transcript_exon_variant	3/4	2

Frequencies

GnomAD3 genomes AF: 0.0378 AC: 5748 AN: 152030 Hom.: 390 Cov.: 34

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0168

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000853

Gnomad OTH AF: 0.0283

GnomAD3 exomes AF: 0.0102 AC: 2556 AN: 249796 Hom.: 151 AF XY: 0.00756 AC XY: 1023 AN XY: 135406

Gnomad AFR exome AF: 0.133

Gnomad AMR exome AF: 0.00724

Gnomad ASJ exome AF: 0.00150

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000850

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000834

Gnomad OTH exome AF: 0.00443

GnomAD4 exome AF: 0.00439 AC: 6414 AN: 1461040 Hom.: 346 Cov.: 72 AF XY: 0.00389 AC XY: 2825 AN XY: 726858

Gnomad4 AFR exome AF: 0.140

Gnomad4 AMR exome AF: 0.00785

Gnomad4 ASJ exome AF: 0.00241

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000916

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.000522

Gnomad4 OTH exome AF: 0.00982

GnomAD4 genome AF: 0.0379 AC: 5768 AN: 152148 Hom.: 394 Cov.: 34 AF XY: 0.0354 AC XY: 2636 AN XY: 74370

Gnomad4 AFR AF: 0.130

Gnomad4 AMR AF: 0.0167

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000854

Gnomad4 OTH AF: 0.0280

Alfa AF: 0.000283 Hom.: 32357

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ExAC AF: 0.0123 AC: 1493

EpiCase AF: 0.00115

EpiControl AF: 0.00136

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.043
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	11
DANN	Benign	0.45
DEOGEN2	Benign	0.059	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-2.2	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.36	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.039
Sift	Benign	0.48	T
Sift4G	Benign	0.21	T
Polyphen		0.0	B
Vest4		0.020
MPC		0.058
ClinPred		0.0016	T
GERP RS		1.8
Varity_R		0.028
gMVP		0.62

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: rs8102086; hg19: chr19-3752874; COSMIC: COSV53661124; COSMIC: COSV53661124;