19-35872540-A-G

Variant names:

• chr19-35872540-A-G
• NM_001024807.3:c.908A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001024807.3(APLP1):​c.908A>G​(p.Glu303Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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: 8.51

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.379809).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APLP1	NM_001024807.3	c.908A>G	p.Glu303Gly	missense_variant	Exon 7 of 17	ENST00000221891.9	NP_001019978.1
APLP1	NM_005166.5	c.908A>G	p.Glu303Gly	missense_variant	Exon 7 of 17		NP_005157.1
APLP1	XM_017026737.3	c.908A>G	p.Glu303Gly	missense_variant	Exon 7 of 16		XP_016882226.1
APLP1	XM_017026738.3	c.908A>G	p.Glu303Gly	missense_variant	Exon 7 of 16		XP_016882227.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APLP1	ENST00000221891.9	c.908A>G	p.Glu303Gly	missense_variant	Exon 7 of 17	1	NM_001024807.3	ENSP00000221891.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 19, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.908A>G (p.E303G) alteration is located in exon 7 (coding exon 7) of the APLP1 gene. This alteration results from a A to G substitution at nucleotide position 908, causing the glutamic acid (E) at amino acid position 303 to be replaced by a glycine (G). 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	0.17
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.048	T;.;.;T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.38	T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.1	.;L;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.6	D;D;.;.
REVEL	Benign	0.23
Sift	Uncertain	0.0020	D;D;.;.
Sift4G	Uncertain	0.010	D;D;D;D
Polyphen		0.20	B;D;D;.
Vest4		0.22
MutPred		0.56		.;Gain of catalytic residue at E303 (P = 0.0925);.;.;
MVP		0.43
MPC		1.2
ClinPred		0.98	D
GERP RS		4.9
gMVP		0.14

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-36363442;