Genetic Variant APLP1:p.Thr111Met (chr19-35870936-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001024807.3(APLP1):c.332C>T(p.Thr111Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000262 in 1,600,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. T111R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

APLP1
NM_001024807.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.96

Publications

3 publications found

Variant links:

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]

APLP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20092416).

BS2

High AC in GnomAdExome4 at 38 AD gene.

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.332C>T	p.Thr111Met	missense	Exon 3 of 17	NP_001019978.1	P51693-2
	APLP1	NM_005166.5		c.332C>T	p.Thr111Met	missense	Exon 3 of 17	NP_005157.1	P51693-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APLP1	ENST00000221891.9	TSL:1 MANE Select	c.332C>T	p.Thr111Met	missense	Exon 3 of 17	ENSP00000221891.4	P51693-2
APLP1	ENST00000960045.1		c.332C>T	p.Thr111Met	missense	Exon 3 of 18	ENSP00000630104.1
APLP1	ENST00000898023.1		c.332C>T	p.Thr111Met	missense	Exon 3 of 17	ENSP00000568082.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000493

AC:

AN:

222940

AF XY:

0.0000500

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000995

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000262

AC:

AN:

1448200

Hom.:

Cov.:

AF XY:

0.0000390

AC XY:

AN XY:

718790

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33372

American (AMR)

AF:

0.00

AC:

AN:

42382

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25678

East Asian (EAS)

AF:

0.00

AC:

AN:

39242

South Asian (SAS)

AF:

0.000324

AC:

AN:

83234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5264

European-Non Finnish (NFE)

AF:

0.00000994

AC:

AN:

1106824

Other (OTH)

AF:

0.00

AC:

AN:

59852

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.000207

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000578

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.040

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.26

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.20

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

1.1

PhyloP100

2.0

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-2.0

REVEL

Benign

0.28

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0040

Polyphen

0.92

Vest4

0.26

MutPred

0.53

Loss of relative solvent accessibility (P = 0.0306)

MVP

0.75

MPC

0.63

ClinPred

0.14

GERP RS

2.6

PromoterAI

-0.012

Neutral

(source)

gMVP

0.30

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over