19-35871880-C-T

Variant names:

• chr19-35871880-C-T
• NM_001024807.3:c.694C>T

Variant summary

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

The NM_001024807.3(APLP1):​c.694C>T​(p.Pro232Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 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: 0.926

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=0.16366652).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APLP1	NM_001024807.3	c.694C>T	p.Pro232Ser	missense_variant	Exon 6 of 17	ENST00000221891.9	NP_001019978.1
APLP1	NM_005166.5	c.694C>T	p.Pro232Ser	missense_variant	Exon 6 of 17		NP_005157.1
APLP1	XM_017026737.3	c.694C>T	p.Pro232Ser	missense_variant	Exon 6 of 16		XP_016882226.1
APLP1	XM_017026738.3	c.694C>T	p.Pro232Ser	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.694C>T	p.Pro232Ser	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

Feb 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.694C>T (p.P232S) alteration is located in exon 6 (coding exon 6) of the APLP1 gene. This alteration results from a C to T substitution at nucleotide position 694, causing the proline (P) at amino acid position 232 to be replaced by a serine (S). 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	0.084
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0013	T;.;.;.;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.16	T;T;T;T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	0.81	.;L;.;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.36	N;N;.;.;.
REVEL	Benign	0.26
Sift	Benign	0.15	T;T;.;.;.
Sift4G	Benign	0.71	T;T;T;T;T
Polyphen		0.18	B;B;B;.;.
Vest4		0.24
MutPred		0.20		.;Gain of phosphorylation at P232 (P = 0.0065);.;.;.;
MVP		0.74
MPC		0.90
ClinPred		0.25	T
GERP RS		0.95
gMVP		0.30

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: chr19-36362782;