4-7433556-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001085382.2(PSAPL1):c.1324G>A(p.Val442Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000587 in 1,611,104 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00050 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00060 ( 2 hom. )

Consequence

PSAPL1
NM_001085382.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.682

Publications

2 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]

PSAPL1 links:

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]

SORCS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05408886).

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSAPL1	NM_001085382.2 link	c.1324G>A	p.Val442Ile	missense_variant	Exon 1 of 1	ENST00000319098.7	NP_001078851.1	Q6NUJ1
SORCS2	NM_020777.3 link	c.548+37201C>T		intron_variant	Intron 2 of 26	ENST00000507866.6	NP_065828.2	Q96PQ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PSAPL1	ENST00000319098.7 link	c.1324G>A	p.Val442Ile	missense_variant	Exon 1 of 1	6	NM_001085382.2	ENSP00000317445.4	Q6NUJ1
SORCS2	ENST00000507866.6 link	c.548+37201C>T		intron_variant	Intron 2 of 26	1	NM_020777.3	ENSP00000422185.2	Q96PQ0
SORCS2	ENST00000511199.1 link	n.163+37201C>T		intron_variant	Intron 2 of 5	4

Frequencies

GnomAD3 genomes

AF:

0.000480

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000705

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000381

AC:

AN:

244138

AF XY:

0.000370

show subpopulations

Gnomad AFR exome

AF:

0.000531

Gnomad AMR exome

AF:

0.0000587

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000677

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000615

Gnomad OTH exome

AF:

0.000336

GnomAD4 exome

AF:

0.000596

AC:

869

AN:

1458796

Hom.:

Cov.:

AF XY:

0.000573

AC XY:

416

AN XY:

725548

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33440

American (AMR)

AF:

0.0000450

AC:

AN:

44426

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26084

East Asian (EAS)

AF:

0.000328

AC:

AN:

39620

South Asian (SAS)

AF:

0.000152

AC:

AN:

85802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52372

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000670

AC:

744

AN:

1110994

Other (OTH)

AF:

0.00139

AC:

AN:

60292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

104

156

208

260

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000499

AC:

AN:

152308

Hom.:

Cov.:

AF XY:

0.000389

AC XY:

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.000385

AC:

AN:

41574

American (AMR)

AF:

0.000261

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000580

AC:

AN:

5168

South Asian (SAS)

AF:

0.000623

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000706

AC:

AN:

68036

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000773

Hom.:

Bravo

AF:

0.000468

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000234

AC:

ESP6500EA

AF:

0.000472

AC:

ExAC

AF:

0.000388

AC:

Asia WGS

AF:

0.00433

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 09, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1324G>A (p.V442I) alteration is located in exon 1 (coding exon 1) of the PSAPL1 gene. This alteration results from a G to A substitution at nucleotide position 1324, causing the valine (V) at amino acid position 442 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

Benign

0.10

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.036

Eigen

Benign

0.11

Eigen_PC

Benign

-0.062

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.47

M_CAP

Benign

0.018

MetaRNN

Benign

0.054

MetaSVM

Uncertain

-0.14

MutationAssessor

Benign

1.8

PhyloP100

0.68

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.77

REVEL

Uncertain

0.41

Sift

Benign

0.071

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.14

MVP

0.97

MPC

0.20

ClinPred

0.022

GERP RS

3.4

Varity_R

0.077

gMVP

0.22

Mutation Taster

=95/5

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

4-7433556-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over