rs4747202

Positions:

• chr10-71817510-G-A

Variant summary

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

The NM_002778.4(PSAP):​c.1540-34C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 1,610,128 control chromosomes in the GnomAD database, including 13,892 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1857 hom., cov: 33)
  • Exomes 𝑓: 0.11 (12035 hom.)
• Consequence: PSAP NM_002778.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0710

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: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 10-71817510-G-A is Benign according to our data. Variant chr10-71817510-G-A is described in ClinVar as [Benign]. Clinvar id is 258811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.353 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSAP	NM_002778.4	c.1540-34C>T		intron_variant		ENST00000394936.8	NP_002769.1
PSAP	NM_001042465.3	c.1549-34C>T		intron_variant			NP_001035930.1
PSAP	NM_001042466.3	c.1546-34C>T		intron_variant			NP_001035931.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSAP	ENST00000394936.8	c.1540-34C>T		intron_variant		1	NM_002778.4	ENSP00000378394	P1

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21256 AN: 151992 Hom.: 1848 Cov.: 33

Gnomad AFR AF: 0.193

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.0629

Gnomad EAS AF: 0.367

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0868

Gnomad OTH AF: 0.124

GnomAD3 exomes AF: 0.154 AC: 38517 AN: 250870 Hom.: 4442 AF XY: 0.141 AC XY: 19167 AN XY: 135654

Gnomad AFR exome AF: 0.198

Gnomad AMR exome AF: 0.317

Gnomad ASJ exome AF: 0.0659

Gnomad EAS exome AF: 0.383

Gnomad SAS exome AF: 0.116

Gnomad FIN exome AF: 0.131

Gnomad NFE exome AF: 0.0835

Gnomad OTH exome AF: 0.131

GnomAD4 exome AF: 0.110 AC: 159703 AN: 1458018 Hom.: 12035 Cov.: 29 AF XY: 0.108 AC XY: 78030 AN XY: 725608

Gnomad4 AFR exome AF: 0.197

Gnomad4 AMR exome AF: 0.304

Gnomad4 ASJ exome AF: 0.0669

Gnomad4 EAS exome AF: 0.389

Gnomad4 SAS exome AF: 0.114

Gnomad4 FIN exome AF: 0.130

Gnomad4 NFE exome AF: 0.0884

Gnomad4 OTH exome AF: 0.121

GnomAD4 genome AF: 0.140 AC: 21280 AN: 152110 Hom.: 1857 Cov.: 33 AF XY: 0.143 AC XY: 10643 AN XY: 74382

Gnomad4 AFR AF: 0.193

Gnomad4 AMR AF: 0.189

Gnomad4 ASJ AF: 0.0629

Gnomad4 EAS AF: 0.366

Gnomad4 SAS AF: 0.128

Gnomad4 FIN AF: 0.127

Gnomad4 NFE AF: 0.0868

Gnomad4 OTH AF: 0.123

Alfa AF: 0.116 Hom.: 375

Bravo AF: 0.154

Asia WGS AF: 0.250 AC: 867 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Combined PSAP deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Krabbe disease due to saposin A deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Sphingolipid activator protein 1 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.1
DANN	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs4747202; hg19: chr10-73577267; COSMIC: COSV56453853; COSMIC: COSV56453853;