rs121918106

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PS1_ModeratePP5_Very_Strong

The NM_002778.4(PSAP):c.1A>T(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000645 in 1,550,968 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000064 ( 0 hom. )

Consequence

PSAP
NM_002778.4 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 3.45

Variant links:

Genes affected

PSAP (HGNC:9498): (prosaposin) This gene encodes a highly conserved preproprotein that is proteolytically processed to generate four main cleavage products including saposins A, B, C, and D. Each domain of the precursor protein is approximately 80 amino acid residues long with nearly identical placement of cysteine residues and glycosylation sites. Saposins A-D localize primarily to the lysosomal compartment where they facilitate the catabolism of glycosphingolipids with short oligosaccharide groups. The precursor protein exists both as a secretory protein and as an integral membrane protein and has neurotrophic activities. Mutations in this gene have been associated with Gaucher disease and metachromatic leukodystrophy. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

PSAP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PS1

Another start lost variant in NM_002778.4 (PSAP) was described as [Pathogenic] in ClinVar as 860182

PP5

Variant 10-71851221-T-A is Pathogenic according to our data. Variant chr10-71851221-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 13365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PSAP	NM_002778.4 linkuse as main transcript	c.1A>T	p.Met1?	start_lost	1/14	ENST00000394936.8
PSAP	NM_001042465.3 linkuse as main transcript	c.1A>T	p.Met1?	start_lost	1/15
PSAP	NM_001042466.3 linkuse as main transcript	c.1A>T	p.Met1?	start_lost	1/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSAP	ENST00000394936.8 linkuse as main transcript	c.1A>T	p.Met1?	start_lost	1/14	1	NM_002778.4	P1	P07602-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152258

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000129

AC:

AN:

154492

Hom.:

AF XY:

0.0000245

AC XY:

AN XY:

81696

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000340

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000643

AC:

AN:

1398710

Hom.:

Cov.:

AF XY:

0.00000725

AC XY:

AN XY:

689912

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000834

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152258

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74390

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

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Gaucher disease due to saposin C deficiency

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Apr 01, 2022	This sequence change in PSAP may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein (PMID: 17616409, 17919309; ClinVar: SCV001231459.2, SCV001590882.1). The highest population minor allele frequency in gnomAD v2.1 is 0.004% (3/74,284 alleles) in the European (non-Finnish) population. This variant has been detected in at least five individuals with PSAP-related disorders with prosaposin deficiency from three unrelated families. Of those individuals, three individuals were homozygous and two siblings were compound heterozygous for the variant and a variant of uncertain significance, confirmed in trans (PMID: 1371116, 15944902, 17919309). Patients with this variant have displayed saposin C deficiency or combined saposin deficiency in fibroblasts/cell extracts (PMID: 1371116, 20484222). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1_Strong, PM3, PP1_Moderate, PM2_Supporting, PP4. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2007	- -

Combined PSAP deficiency

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2007

- -

Sphingolipid activator protein 1 deficiency

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 21, 2023

For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of the initiator codon alters PSAP gene expression (PMID: 20484222). ClinVar contains an entry for this variant (Variation ID: 13365). This variant is also known as M1L. Disruption of the initiator codon has been observed in individuals with PSAP-related conditions (PMID: 1371116, 17616409, 20484222). This variant is present in population databases (rs121918106, gnomAD 0.004%). This sequence change affects the initiator methionine of the PSAP mRNA. The next in-frame methionine is located at codon 76. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.21

Cadd

Benign

Dann

Benign

0.85

DEOGEN2

Benign

0.23

T;T;T

Eigen

Benign

0.14

Eigen_PC

Benign

0.16

FATHMM_MKL

Benign

0.59

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Benign

-0.58

MutationTaster

Benign

1.0

A;A;A

PROVEAN

Benign

-0.45

N;.;N

REVEL

Uncertain

0.41

Sift

Benign

0.091

T;.;T

Sift4G

Benign

0.79

T;T;T

Polyphen

0.70

P;.;.

Vest4

0.76

MutPred

0.91

Loss of solvent accessibility (P = 0.0152);Loss of solvent accessibility (P = 0.0152);Loss of solvent accessibility (P = 0.0152);

MVP

0.94

ClinPred

0.97

GERP RS

5.0

Varity_R

0.68

gMVP

0.49

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over