19-3752876-A-G

Position:

• chr19-3752876-A-G

Variant summary

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

The NM_004886.4(APBA3):​c.1126T>C​(p.Cys376Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.548 in 1,613,094 control chromosomes in the GnomAD database, including 245,557 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.51 (20797 hom., cov: 34)
  • Exomes 𝑓: 0.55 (224760 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=1.1344377E-5).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.64 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APBA3	NM_004886.4	c.1126T>C	p.Cys376Arg	missense_variant	7/11	ENST00000316757.4	NP_004877.1
APBA3	XM_006722950.5	c.1126T>C	p.Cys376Arg	missense_variant	7/10		XP_006723013.1
APBA3	XM_006722951.4	c.400T>C	p.Cys134Arg	missense_variant	5/8		XP_006723014.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APBA3	ENST00000316757.4	c.1126T>C	p.Cys376Arg	missense_variant	7/11	1	NM_004886.4	ENSP00000315136.2
APBA3	ENST00000590064.1	n.3397T>C		non_coding_transcript_exon_variant	1/4	1
APBA3	ENST00000588984.5	n.970T>C		non_coding_transcript_exon_variant	4/8	2
APBA3	ENST00000592826.1	n.400T>C		non_coding_transcript_exon_variant	3/4	2

Frequencies

GnomAD3 genomes AF: 0.511 AC: 77613 AN: 152004 Hom.: 20782 Cov.: 34

Gnomad AFR AF: 0.352

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.651

Gnomad ASJ AF: 0.558

Gnomad EAS AF: 0.651

Gnomad SAS AF: 0.574

Gnomad FIN AF: 0.582

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.547

Gnomad OTH AF: 0.553

GnomAD3 exomes AF: 0.572 AC: 142999 AN: 249796 Hom.: 41977 AF XY: 0.570 AC XY: 77160 AN XY: 135406

Gnomad AFR exome AF: 0.350

Gnomad AMR exome AF: 0.728

Gnomad ASJ exome AF: 0.559

Gnomad EAS exome AF: 0.649

Gnomad SAS exome AF: 0.566

Gnomad FIN exome AF: 0.565

Gnomad NFE exome AF: 0.548

Gnomad OTH exome AF: 0.585

GnomAD4 exome AF: 0.552 AC: 806737 AN: 1460972 Hom.: 224760 Cov.: 72 AF XY: 0.552 AC XY: 401131 AN XY: 726830

Gnomad4 AFR exome AF: 0.342

Gnomad4 AMR exome AF: 0.719

Gnomad4 ASJ exome AF: 0.557

Gnomad4 EAS exome AF: 0.679

Gnomad4 SAS exome AF: 0.558

Gnomad4 FIN exome AF: 0.566

Gnomad4 NFE exome AF: 0.546

Gnomad4 OTH exome AF: 0.548

GnomAD4 genome AF: 0.511 AC: 77683 AN: 152122 Hom.: 20797 Cov.: 34 AF XY: 0.516 AC XY: 38339 AN XY: 74358

Gnomad4 AFR AF: 0.353

Gnomad4 AMR AF: 0.651

Gnomad4 ASJ AF: 0.558

Gnomad4 EAS AF: 0.651

Gnomad4 SAS AF: 0.574

Gnomad4 FIN AF: 0.582

Gnomad4 NFE AF: 0.547

Gnomad4 OTH AF: 0.558

Alfa AF: 0.552 Hom.: 32357

Bravo AF: 0.530

TwinsUK AF: 0.529 AC: 1963

ALSPAC AF: 0.542 AC: 2087

ESP6500AA AF: 0.410 AC: 1804

ESP6500EA AF: 0.552 AC: 4742

ExAC AF: 0.561 AC: 68098

EpiCase AF: 0.549

EpiControl AF: 0.553

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	12
DANN	Benign	0.73
DEOGEN2	Benign	0.080	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.10	T
MetaRNN	Benign	0.000011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	3.0	N
REVEL	Benign	0.061
Sift	Benign	0.30	T
Sift4G	Benign	0.17	T
Polyphen		0.0	B
Vest4		0.023
MPC		0.078
ClinPred		0.0011	T
GERP RS		1.8
Varity_R		0.048
gMVP		0.74

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: COSV53661515; COSMIC: COSV53661515;