19-3751034-A-G

Variant names:

• chr19-3751034-A-G
• rs1356226308
• NM_004886.4:c.1720T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004886.4(APBA3):​c.1720T>C​(p.Tyr574His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000071 in 1,407,522 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: APBA3 NM_004886.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.67

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APBA3	NM_004886.4	c.1720T>C	p.Tyr574His	missense_variant	Exon 11 of 11	ENST00000316757.4	NP_004877.1
TJP3	NM_001267560.2	c.*350A>G		downstream_gene_variant		ENST00000541714.7	NP_001254489.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APBA3	ENST00000316757.4	c.1720T>C	p.Tyr574His	missense_variant	Exon 11 of 11	1	NM_004886.4	ENSP00000315136.2
TJP3	ENST00000541714.7	c.*350A>G		downstream_gene_variant		2	NM_001267560.2	ENSP00000439278.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000597 AC: 1 AN: 167572 Hom.: 0 AF XY: 0.0000113 AC XY: 1 AN XY: 88750

Gnomad AFR exome AF: 0.000104

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1407522 Hom.: 0 Cov.: 32 AF XY: 0.00000144 AC XY: 1 AN XY: 695036

Gnomad4 AFR exome AF: 0.0000312

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1720T>C (p.Y574H) alteration is located in exon 11 (coding exon 10) of the APBA3 gene. This alteration results from a T to C substitution at nucleotide position 1720, causing the tyrosine (Y) at amino acid position 574 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Benign	0.23
Sift	Uncertain	0.016	D
Sift4G	Benign	0.085	T
Polyphen		1.0	D
Vest4		0.50
MutPred		0.32		Gain of relative solvent accessibility (P = 0.0249);
MVP		0.39
MPC		0.36
ClinPred		0.93	D
GERP RS		4.6
Varity_R		0.34
gMVP		0.95

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: rs1356226308; hg19: chr19-3751032;