NM_004886.4:c.1720T>C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• 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 2 ACMG points.

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

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.1720T>C	p.Tyr574His	missense	Exon 11 of 11	NP_004877.1	O96018
	TJP3	NM_001267560.2	MANE Select	c.*350A>G		downstream_gene	N/A	NP_001254489.1	O95049-1
	TJP3	NM_001267561.2		c.*350A>G		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.1720T>C	p.Tyr574His	missense	Exon 11 of 11	ENSP00000315136.2	O96018
	APBA3	ENST00000590064.1	TSL:1	n.4095T>C		non_coding_transcript_exon	Exon 4 of 4
	APBA3	ENST00000861573.1		c.1768T>C	p.Tyr590His	missense	Exon 12 of 12	ENSP00000531632.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000597 AC: 1 AN: 167572 AF XY: 0.0000113

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 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

African (AFR) AF: 0.0000312 AC: 1 AN: 32084

American (AMR) AF: 0.00 AC: 0 AN: 36558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25242

East Asian (EAS) AF: 0.00 AC: 0 AN: 36498

South Asian (SAS) AF: 0.00 AC: 0 AN: 79802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49612

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1083654

Other (OTH) AF: 0.00 AC: 0 AN: 58366

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		8.7
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
Mutation Taster		=51/49	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: rs1356226308; hg19: chr19-3751032;