19-35871943-G-T

Position:

• chr19-35871943-G-T

Variant summary

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

The ENST00000221891.9(APLP1):​c.757G>T​(p.Val253Leu) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: APLP1 ENST00000221891.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.67

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=0.30516443).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APLP1	NM_001024807.3	c.757G>T	p.Val253Leu	missense_variant	6/17	ENST00000221891.9	NP_001019978.1
APLP1	NM_005166.5	c.757G>T	p.Val253Leu	missense_variant	6/17		NP_005157.1
APLP1	XM_017026737.3	c.757G>T	p.Val253Leu	missense_variant	6/16		XP_016882226.1
APLP1	XM_017026738.3	c.757G>T	p.Val253Leu	missense_variant	6/16		XP_016882227.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APLP1	ENST00000221891.9	c.757G>T	p.Val253Leu	missense_variant	6/17	1	NM_001024807.3	ENSP00000221891.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 26, 2024

The c.757G>T (p.V253L) alteration is located in exon 6 (coding exon 6) of the APLP1 gene. This alteration results from a G to T substitution at nucleotide position 757, causing the valine (V) at amino acid position 253 to be replaced by a leucine (L). 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	0.14
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.013	T;.;.;.;T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.31	T;T;T;T;T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	0.46	.;N;.;.;.
MutationTaster	Benign	0.69	D;D;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.83	N;N;.;.;.
REVEL	Uncertain	0.40
Sift	Benign	0.25	T;T;.;.;.
Sift4G	Benign	0.69	T;T;T;T;T
Polyphen		0.87	P;P;D;.;.
Vest4		0.29
MutPred		0.13		.;Gain of helix (P = 0.2684);.;.;.;
MVP		0.85
MPC		1.1
ClinPred		0.66	D
GERP RS		4.6
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1431429331; hg19: chr19-36362845;