rs121918106

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong

The NM_002778.4(PSAP):c.1A>T(p.Met1?) variant causes a initiator codon 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 initiator_codon

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.45

Publications

13 publications found

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 Gene-Disease associations (from GenCC):

combined PSAP deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)
Gaucher disease due to saposin C deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
Krabbe disease due to saposin A deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, G2P
metachromatic leukodystrophy due to saposin B deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
Parkinson disease 24, autosomal dominant, susceptibility to
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

PSAP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 20 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 11 pathogenic variants. Next in-frame start position is after 76 codons. Genomic position: 71831869. Lost 0.143 part of the original CDS.

PS1

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

PM2

Very rare variant in population databases, with high coverage;

PP5

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSAP	NM_002778.4 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 14	ENST00000394936.8	NP_002769.1	P07602-1A0A024QZQ2
PSAP	NM_001042465.3 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 15		NP_001035930.1	P07602-3
PSAP	NM_001042466.3 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 15		NP_001035931.1	P07602-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSAP	ENST00000394936.8 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 14	1	NM_002778.4	ENSP00000378394.3		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

GnomAD2 exomes

AF:

0.0000129

AC:

AN:

154492

AF XY:

0.0000245

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:

0.0000340

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

African (AFR)

AF:

0.00

AC:

AN:

31588

American (AMR)

AF:

0.00

AC:

AN:

35700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25170

East Asian (EAS)

AF:

0.00

AC:

AN:

35732

South Asian (SAS)

AF:

0.00

AC:

AN:

79232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48792

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00000834

AC:

AN:

1078812

Other (OTH)

AF:

0.00

AC:

AN:

57986

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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:

0.00000657

AC:

AN:

152258

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74390

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41474

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

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

Dec 01, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Apr 01, 2022

Molecular Genetics, Royal Melbourne Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Combined PSAP deficiency

Pathogenic:1

Dec 01, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Sphingolipid activator protein 1 deficiency

Pathogenic:1

Sep 21, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.21

CADD

Benign

(source)

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

PhyloP100

3.4

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

PromoterAI

-0.18

Neutral

(source)

Varity_R

0.68

gMVP

0.49

Mutation Taster

=6/194

disease causing (ClinVar)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over