rs1554879741

Positions:

• chr10-71819093-C-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_002778.4(PSAP):​c.1369G>T​(p.Glu457*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PSAP NM_002778.4 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.323

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-71819093-C-A is Pathogenic according to our data. Variant chr10-71819093-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 438801.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSAP	NM_002778.4	c.1369G>T	p.Glu457*	stop_gained	12/14	ENST00000394936.8	NP_002769.1
PSAP	NM_001042465.3	c.1378G>T	p.Glu460*	stop_gained	13/15		NP_001035930.1
PSAP	NM_001042466.3	c.1375G>T	p.Glu459*	stop_gained	13/15		NP_001035931.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSAP	ENST00000394936.8	c.1369G>T	p.Glu457*	stop_gained	12/14	1	NM_002778.4	ENSP00000378394.3
PSAP	ENST00000495196.1	n.179G>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Sphingolipid activator protein 1 deficiency;C1864651:Gaucher disease due to saposin C deficiency;C2673266:Krabbe disease due to saposin A deficiency;C2673635:Combined PSAP deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

research

Donald Williams Parsons Laboratory, Baylor College of Medicine

Jun 18, 2013

This nonsense variant is categorized as deleterious according to ACMG guidelines (PMID:18414213). It would be pathogenic in a recessive state; heterozygotes would be carriers for the condition. It was found once in our study heterozygous, maternally inherited in a 2-month-old female with choroid plexus carcinoma, seizures, dysmorphic features, genital anomalies, and congenital bowel obstruction. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2024

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has been reported as a single heterozygous incidental finding in a child with seizures, abnormal facies, and congential anomalies (Parsons et al., 2016); This variant is associated with the following publications: (PMID: 26822237) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	35
DANN	Uncertain	0.98
Eigen	Uncertain	0.20
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.58	D
Vest4		0.93
GERP RS		-0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Other links and lift over

dbSNP: rs1554879741; hg19: chr10-73578850;