19-35871973-G-A

Variant names:

• chr19-35871973-G-A
• NM_001024807.3:c.787G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001024807.3(APLP1):​c.787G>A​(p.Ala263Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: APLP1 NM_001024807.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.62

Genes affected

APLP1 (HGNC:597): (amyloid beta precursor like protein 1) This gene encodes a member of the highly conserved amyloid precursor protein gene family. The encoded protein is a membrane-associated glycoprotein that is cleaved by secretases in a manner similar to amyloid beta A4 precursor protein cleavage. This cleavage liberates an intracellular cytoplasmic fragment that may act as a transcriptional activator. The encoded protein may also play a role in synaptic maturation during cortical development. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18993807).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APLP1	NM_001024807.3	c.787G>A	p.Ala263Thr	missense_variant	Exon 6 of 17	ENST00000221891.9	NP_001019978.1
APLP1	NM_005166.5	c.787G>A	p.Ala263Thr	missense_variant	Exon 6 of 17		NP_005157.1
APLP1	XM_017026737.3	c.787G>A	p.Ala263Thr	missense_variant	Exon 6 of 16		XP_016882226.1
APLP1	XM_017026738.3	c.787G>A	p.Ala263Thr	missense_variant	Exon 6 of 16		XP_016882227.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APLP1	ENST00000221891.9	c.787G>A	p.Ala263Thr	missense_variant	Exon 6 of 17	1	NM_001024807.3	ENSP00000221891.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 11, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.787G>A (p.A263T) alteration is located in exon 6 (coding exon 6) of the APLP1 gene. This alteration results from a G to A substitution at nucleotide position 787, causing the alanine (A) at amino acid position 263 to be replaced by a threonine (T). 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	Benign	0.071
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0030	T;.;.;.;T
Eigen	Benign	-0.029
Eigen_PC	Benign	0.040
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.90	D;D;D;T;T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.19	T;T;T;T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	0.81	.;L;.;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.11	N;N;.;.;.
REVEL	Benign	0.23
Sift	Benign	0.38	T;T;.;.;.
Sift4G	Benign	0.47	T;T;T;T;T
Polyphen		0.95	P;D;P;.;.
Vest4		0.29
MutPred		0.17		.;Gain of phosphorylation at A263 (P = 0.0198);.;.;.;
MVP		0.88
MPC		1.0
ClinPred		0.75	D
GERP RS		3.6
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-36362875;