NM_004886.4:c.1126T>C

Variant names:

• chr19-3752876-A-G
• rs8102086
• NM_004886.4:c.1126T>C

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 35 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
APBA3	NM_004886.4	c.1126T>C	p.Cys376Arg	missense_variant	Exon 7 of 11	ENST00000316757.4	NP_004877.1
APBA3	XM_006722950.5	c.1126T>C	p.Cys376Arg	missense_variant	Exon 7 of 10		XP_006723013.1
APBA3	XM_006722951.4	c.400T>C	p.Cys134Arg	missense_variant	Exon 5 of 8		XP_006723014.1

Ensembl

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

GnomAD2 exomes AF: 0.572 AC: 142999 AN: 249796 AF XY: 0.570

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 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

African (AFR) AF: 0.342 AC: 11458 AN: 33474

American (AMR) AF: 0.719 AC: 32147 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.557 AC: 14547 AN: 26120

East Asian (EAS) AF: 0.679 AC: 26945 AN: 39684

South Asian (SAS) AF: 0.558 AC: 48103 AN: 86254

European-Finnish (FIN) AF: 0.566 AC: 29864 AN: 52724

Middle Eastern (MID) AF: 0.532 AC: 3071 AN: 5768

European-Non Finnish (NFE) AF: 0.546 AC: 607501 AN: 1111862

Other (OTH) AF: 0.548 AC: 33101 AN: 60370

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

African (AFR) AF: 0.353 AC: 14644 AN: 41526

American (AMR) AF: 0.651 AC: 9963 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.558 AC: 1937 AN: 3472

East Asian (EAS) AF: 0.651 AC: 3352 AN: 5152

South Asian (SAS) AF: 0.574 AC: 2767 AN: 4818

European-Finnish (FIN) AF: 0.582 AC: 6168 AN: 10600

Middle Eastern (MID) AF: 0.510 AC: 150 AN: 294

European-Non Finnish (NFE) AF: 0.547 AC: 37165 AN: 67940

Other (OTH) AF: 0.558 AC: 1176 AN: 2108

Alfa AF: 0.553 Hom.: 51411

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
PhyloP100		0.97
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
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8102086; hg19: chr19-3752874; COSMIC: COSV53661515; COSMIC: COSV53661515;