rs4747203

Positions:

• chr10-71819125-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000394936.8(PSAP):​c.1351-14A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.308 in 1,609,564 control chromosomes in the GnomAD database, including 81,465 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.34 (9632 hom., cov: 32)
  • Exomes 𝑓: 0.30 (71833 hom.)
• Consequence: PSAP ENST00000394936.8 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -0.532

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: This place is a probable branch point but likely benign (scored 3 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 10-71819125-T-C is Benign according to our data. Variant chr10-71819125-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 94085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.599 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSAP	NM_002778.4	c.1351-14A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000394936.8	NP_002769.1
PSAP	NM_001042465.3	c.1360-14A>G		splice_polypyrimidine_tract_variant, intron_variant			NP_001035930.1
PSAP	NM_001042466.3	c.1357-14A>G		splice_polypyrimidine_tract_variant, intron_variant			NP_001035931.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSAP	ENST00000394936.8	c.1351-14A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_002778.4	ENSP00000378394	P1
PSAP	ENST00000495196.1	n.147A>G		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52311 AN: 151910 Hom.: 9609 Cov.: 32

Gnomad AFR AF: 0.440

Gnomad AMI AF: 0.263

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.617

Gnomad SAS AF: 0.279

Gnomad FIN AF: 0.353

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.327

GnomAD3 exomes AF: 0.341 AC: 85103 AN: 249526 Hom.: 15916 AF XY: 0.326 AC XY: 43998 AN XY: 134902

Gnomad AFR exome AF: 0.450

Gnomad AMR exome AF: 0.445

Gnomad ASJ exome AF: 0.239

Gnomad EAS exome AF: 0.622

Gnomad SAS exome AF: 0.268

Gnomad FIN exome AF: 0.352

Gnomad NFE exome AF: 0.277

Gnomad OTH exome AF: 0.305

GnomAD4 exome AF: 0.304 AC: 443173 AN: 1457536 Hom.: 71833 Cov.: 33 AF XY: 0.300 AC XY: 217451 AN XY: 725230

Gnomad4 AFR exome AF: 0.449

Gnomad4 AMR exome AF: 0.436

Gnomad4 ASJ exome AF: 0.242

Gnomad4 EAS exome AF: 0.665

Gnomad4 SAS exome AF: 0.266

Gnomad4 FIN exome AF: 0.351

Gnomad4 NFE exome AF: 0.284

Gnomad4 OTH exome AF: 0.314

GnomAD4 genome AF: 0.344 AC: 52371 AN: 152028 Hom.: 9632 Cov.: 32 AF XY: 0.348 AC XY: 25851 AN XY: 74290

Gnomad4 AFR AF: 0.441

Gnomad4 AMR AF: 0.358

Gnomad4 ASJ AF: 0.237

Gnomad4 EAS AF: 0.617

Gnomad4 SAS AF: 0.278

Gnomad4 FIN AF: 0.353

Gnomad4 NFE AF: 0.273

Gnomad4 OTH AF: 0.324

Alfa AF: 0.301 Hom.: 2237

Bravo AF: 0.356

Asia WGS AF: 0.413 AC: 1438 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 22, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Sphingolipid activator protein 1 deficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 26, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Combined PSAP deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Krabbe disease due to saposin A deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Atypical Gaucher Disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Gaucher disease due to saposin C deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

CDH23-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Galactosylceramide beta-galactosidase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Metachromatic leukodystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.75
DANN	Benign	0.73
BranchPoint Hunter		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4747203; hg19: chr10-73578882;