19-35871020-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_ModerateBS2

The NM_001024807.3(APLP1):​c.416G>A​(p.Arg139His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000719 in 1,530,726 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000073 ( 0 hom. )

Consequence

APLP1
NM_001024807.3 missense

Scores

6
13

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0960
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP6
Variant 19-35871020-G-A is Benign according to our data. Variant chr19-35871020-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3127854.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
APLP1NM_001024807.3 linkuse as main transcriptc.416G>A p.Arg139His missense_variant 3/17 ENST00000221891.9 NP_001019978.1
APLP1NM_005166.5 linkuse as main transcriptc.416G>A p.Arg139His missense_variant 3/17 NP_005157.1
APLP1XM_017026737.3 linkuse as main transcriptc.416G>A p.Arg139His missense_variant 3/16 XP_016882226.1
APLP1XM_017026738.3 linkuse as main transcriptc.416G>A p.Arg139His missense_variant 3/16 XP_016882227.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
APLP1ENST00000221891.9 linkuse as main transcriptc.416G>A p.Arg139His missense_variant 3/171 NM_001024807.3 ENSP00000221891 P4P51693-2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152208
Hom.:
0
Cov.:
32
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:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000725
AC:
10
AN:
1378518
Hom.:
0
Cov.:
31
AF XY:
0.00000737
AC XY:
5
AN XY:
678378
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000307
Gnomad4 ASJ exome
AF:
0.0000440
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000134
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000560
Gnomad4 OTH exome
AF:
0.0000176
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152208
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.00000858
AC:
1

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJan 03, 2024This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.062
BayesDel_addAF
Uncertain
0.015
T
BayesDel_noAF
Benign
-0.22
CADD
Benign
18
DANN
Uncertain
0.98
DEOGEN2
Benign
0.10
T;.;.;.;T
Eigen
Benign
-0.76
Eigen_PC
Benign
-0.72
FATHMM_MKL
Benign
0.46
N
LIST_S2
Uncertain
0.87
D;T;D;D;D
M_CAP
Uncertain
0.13
D
MetaRNN
Uncertain
0.49
T;T;T;T;T
MetaSVM
Benign
-0.61
T
MutationAssessor
Benign
1.4
.;L;.;.;.
MutationTaster
Benign
0.92
D;D;D
PrimateAI
Benign
0.29
T
PROVEAN
Benign
-2.2
N;N;.;.;.
REVEL
Uncertain
0.36
Sift
Benign
0.26
T;T;.;.;.
Sift4G
Benign
0.26
T;T;T;T;T
Polyphen
0.020
B;B;B;.;.
Vest4
0.17
MutPred
0.76
.;Loss of sheet (P = 0.1158);.;.;.;
MVP
0.64
MPC
0.43
ClinPred
0.057
T
GERP RS
-6.5
gMVP
0.48

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs775672735; hg19: chr19-36361922; COSMIC: COSV105837801; COSMIC: COSV105837801; API