chr19-35873645-C-A

Position:

• chr19-35873645-C-A

Variant summary

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

The ENST00000221891.9(APLP1):​c.988C>A​(p.Arg330Ser) 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: 32)
• Consequence: APLP1 ENST00000221891.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.36

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=0.30860212).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APLP1	NM_001024807.3	c.988C>A	p.Arg330Ser	missense_variant	8/17	ENST00000221891.9	NP_001019978.1
APLP1	NM_005166.5	c.988C>A	p.Arg330Ser	missense_variant	8/17		NP_005157.1
APLP1	XM_017026737.3	c.988C>A	p.Arg330Ser	missense_variant	8/16		XP_016882226.1
APLP1	XM_017026738.3	c.988C>A	p.Arg330Ser	missense_variant	8/16		XP_016882227.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APLP1	ENST00000221891.9	c.988C>A	p.Arg330Ser	missense_variant	8/17	1	NM_001024807.3	ENSP00000221891.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Nov 14, 2023

The c.988C>A (p.R330S) alteration is located in exon 8 (coding exon 8) of the APLP1 gene. This alteration results from a C to A substitution at nucleotide position 988, causing the arginine (R) at amino acid position 330 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	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;.;.;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.31	T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.7	.;L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.1	D;D;.;.
REVEL	Benign	0.11
Sift	Uncertain	0.0010	D;D;.;.
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		0.42	B;P;D;.
Vest4		0.48
MutPred		0.37		.;Loss of MoRF binding (P = 0.0116);.;.;
MVP		0.56
MPC		0.81
ClinPred		0.98	D
GERP RS		3.9
gMVP		0.36

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: chr19-36364547;