chr19-35869689-C-T

Variant names:

• chr19-35869689-C-T
• rs748077934
• NM_001024807.3:c.170C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001024807.3(APLP1):​c.170C>T​(p.Ala57Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: APLP1 NM_001024807.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.57
• Publications: 3 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.892

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.170C>T	p.Ala57Val	missense	Exon 2 of 17	NP_001019978.1	P51693-2
	APLP1	NM_005166.5		c.170C>T	p.Ala57Val	missense	Exon 2 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.170C>T	p.Ala57Val	missense	Exon 2 of 17	ENSP00000221891.4	P51693-2
	APLP1	ENST00000960045.1		c.170C>T	p.Ala57Val	missense	Exon 2 of 18	ENSP00000630104.1
	APLP1	ENST00000898023.1		c.170C>T	p.Ala57Val	missense	Exon 2 of 17	ENSP00000568082.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000122 AC: 3 AN: 245706 AF XY: 0.0000224

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000165

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459336 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 725924

African (AFR) AF: 0.00 AC: 0 AN: 33398

American (AMR) AF: 0.00 AC: 0 AN: 44302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26044

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52970

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5430

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111248

Other (OTH) AF: 0.00 AC: 0 AN: 60198

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.6
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.70		Gain of sheet (P = 0.0221)
MVP		0.89
MPC		1.1
ClinPred		0.96	D
GERP RS		4.0
PromoterAI		0.020	Neutral
gMVP		0.90
Mutation Taster		=38/62	disease causing

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

Other links and lift over

dbSNP: rs748077934; hg19: chr19-36360591;