NM_001024807.3:c.446C>T

Variant names:

• chr19-35871258-C-T
• rs200445460
• NM_001024807.3:c.446C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001024807.3(APLP1):​c.446C>T​(p.Ala149Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A149D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: APLP1 NM_001024807.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.42
• Publications: 2 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001024807.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APLP1	NM_001024807.3	MANE Select	c.446C>T	p.Ala149Val	missense	Exon 4 of 17	NP_001019978.1	P51693-2
	APLP1	NM_005166.5		c.446C>T	p.Ala149Val	missense	Exon 4 of 17	NP_005157.1	P51693-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APLP1	ENST00000221891.9	TSL:1 MANE Select	c.446C>T	p.Ala149Val	missense	Exon 4 of 17	ENSP00000221891.4	P51693-2
	APLP1	ENST00000960045.1		c.446C>T	p.Ala149Val	missense	Exon 4 of 18	ENSP00000630104.1
	APLP1	ENST00000898023.1		c.446C>T	p.Ala149Val	missense	Exon 4 of 17	ENSP00000568082.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461278 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726880

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111786

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	22
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.036	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Benign	1.2	L
PhyloP100		5.4
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.6	N
REVEL	Pathogenic	0.69
Sift	Benign	0.40	T
Sift4G	Benign	0.57	T
Polyphen		0.98	D
Vest4		0.38
MutPred		0.78		Gain of sheet (P = 0.0344)
MVP		0.85
MPC		1.1
ClinPred		0.92	D
GERP RS		3.7
gMVP		0.73
Mutation Taster		=35/65	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs200445460; hg19: chr19-36362160;