rs764586181

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001085382.2(PSAPL1):​c.1475G>T​(p.Ser492Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000738 in 1,354,958 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

PSAPL1
NM_001085382.2 missense

Scores

2
6
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.429

Publications

0 publications found
Variant links:
Genes affected
PSAPL1 (HGNC:33131): (prosaposin like 1) This gene encodes a protein that is related to the glycoprotein prosaposin. Based on sequence similarity between the encoded protein and prosaposin, it is predicted that the encoded protein is a preproprotein that is proteolytically processed to generate multiple protein products. These predicted products include saposins A-like, B-like, C-like, and D-like, which may play a role in the lysosomal degradation of sphingolipids. [provided by RefSeq, Jul 2015]
SORCS2 (HGNC:16698): (sortilin related VPS10 domain containing receptor 2) This gene encodes one family member of vacuolar protein sorting 10 (VPS10) domain-containing receptor proteins. The VPS10 domain name comes from the yeast carboxypeptidase Y sorting receptor Vps10 protein. Members of this gene family are large with many exons but the CDS lengths are usually less than 3700 nt. Very large introns typically separate the exons encoding the VPS10 domain; the remaining exons are separated by much smaller-sized introns. These genes are strongly expressed in the central nervous system. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PSAPL1NM_001085382.2 linkc.1475G>T p.Ser492Ile missense_variant Exon 1 of 1 ENST00000319098.7 NP_001078851.1 Q6NUJ1
SORCS2NM_020777.3 linkc.548+37050C>A intron_variant Intron 2 of 26 ENST00000507866.6 NP_065828.2 Q96PQ0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PSAPL1ENST00000319098.7 linkc.1475G>T p.Ser492Ile missense_variant Exon 1 of 1 6 NM_001085382.2 ENSP00000317445.4 Q6NUJ1
SORCS2ENST00000507866.6 linkc.548+37050C>A intron_variant Intron 2 of 26 1 NM_020777.3 ENSP00000422185.2 Q96PQ0
SORCS2ENST00000511199.1 linkn.163+37050C>A intron_variant Intron 2 of 5 4

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
AF:
7.38e-7
AC:
1
AN:
1354958
Hom.:
0
Cov.:
58
AF XY:
0.00000151
AC XY:
1
AN XY:
662990
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
30064
American (AMR)
AF:
0.00
AC:
0
AN:
27330
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
19948
East Asian (EAS)
AF:
0.00
AC:
0
AN:
38110
South Asian (SAS)
AF:
0.00
AC:
0
AN:
68350
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
48528
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5306
European-Non Finnish (NFE)
AF:
9.42e-7
AC:
1
AN:
1061458
Other (OTH)
AF:
0.00
AC:
0
AN:
55864
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
34

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Apr 10, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.1475G>T (p.S492I) alteration is located in exon 1 (coding exon 1) of the PSAPL1 gene. This alteration results from a G to T substitution at nucleotide position 1475, causing the serine (S) at amino acid position 492 to be replaced by an isoleucine (I). 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
0.70
BayesDel_addAF
Benign
-0.024
T
BayesDel_noAF
Benign
-0.27
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.070
T
Eigen
Benign
-0.053
Eigen_PC
Benign
-0.31
FATHMM_MKL
Benign
0.12
N
LIST_S2
Benign
0.38
T
M_CAP
Benign
0.0062
T
MetaRNN
Uncertain
0.53
D
MetaSVM
Benign
-0.80
T
MutationAssessor
Uncertain
2.6
M
PhyloP100
0.43
PrimateAI
Uncertain
0.57
T
PROVEAN
Uncertain
-4.2
D
REVEL
Benign
0.20
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0040
D
Polyphen
1.0
D
Vest4
0.33
MutPred
0.69
Gain of helix (P = 0.027);
MVP
0.79
MPC
0.23
ClinPred
0.92
D
GERP RS
1.2
Varity_R
0.67
gMVP
0.54
Mutation Taster
=98/2
polymorphism

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

Other links and lift over

dbSNP: rs764586181; hg19: chr4-7435132; COSMIC: COSV59843635; API