19-3751037-C-A

Variant names:

• chr19-3751037-C-A
• rs199580985
• NM_004886.4:c.1717G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004886.4(APBA3):​c.1717G>T​(p.Val573Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000852 in 1,408,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. V573M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000085 (0 hom.)
• Consequence: APBA3 NM_004886.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.689
• Publications: 0 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]

TJP3 (HGNC:11829): (tight junction protein 3) The protein encoded by this gene is a member of the membrane-associated guanylate kinase-like (MAGUK) protein family which is characterized by members having multiple PDZ domains, a single SH3 domain, and a single guanylate kinase-like (GUK)-domain. In addition, members of the zonula occludens protein subfamily have an acidic domain, a basic arginine-rich region, and a proline-rich domain. The protein encoded by this gene plays a role in the linkage between the actin cytoskeleton and tight-junctions and also sequesters cyclin D1 at tight junctions during mitosis. Alternative splicing results in multiple transcript variants encoding distinct isoforms. This gene has a partial pseudogene on chromosome 1. [provided by RefSeq, May 2012]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1052427).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004886.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APBA3	NM_004886.4	MANE Select	c.1717G>T	p.Val573Leu	missense	Exon 11 of 11	NP_004877.1	O96018
	TJP3	NM_001267560.2	MANE Select	c.*353C>A		downstream_gene	N/A	NP_001254489.1	O95049-1
	TJP3	NM_001267561.2		c.*353C>A		downstream_gene	N/A	NP_001254490.1	O95049-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APBA3	ENST00000316757.4	TSL:1 MANE Select	c.1717G>T	p.Val573Leu	missense	Exon 11 of 11	ENSP00000315136.2	O96018
	APBA3	ENST00000590064.1	TSL:1	n.4092G>T		non_coding_transcript_exon	Exon 4 of 4
	APBA3	ENST00000861573.1		c.1765G>T	p.Val589Leu	missense	Exon 12 of 12	ENSP00000531632.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000852 AC: 12 AN: 1408484 Hom.: 0 Cov.: 32 AF XY: 0.00000431 AC XY: 3 AN XY: 695570

African (AFR) AF: 0.00 AC: 0 AN: 32116

American (AMR) AF: 0.00 AC: 0 AN: 36664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25260

East Asian (EAS) AF: 0.00 AC: 0 AN: 36596

South Asian (SAS) AF: 0.00 AC: 0 AN: 79866

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49678

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.0000111 AC: 12 AN: 1084204

Other (OTH) AF: 0.00 AC: 0 AN: 58394

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Benign	0.067	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.91	L
PhyloP100		0.69
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.019
Sift	Benign	0.27	T
Sift4G	Benign	0.55	T
Polyphen		0.013	B
Vest4		0.12
MutPred		0.30		Gain of catalytic residue at V573 (P = 0.0441)
MVP		0.19
MPC		0.049
ClinPred		0.34	T
GERP RS		0.84
Varity_R		0.046
gMVP		0.53
Mutation Taster		=91/9	polymorphism

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: rs199580985; hg19: chr19-3751035;