10-71821844-C-A

Position:

• chr10-71821844-C-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.909+32G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0746 in 1,613,710 control chromosomes in the GnomAD database, including 5,013 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (368 hom., cov: 32)
  • Exomes 𝑓: 0.076 (4645 hom.)
• Consequence: PSAP NM_002778.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.53

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 10-71821844-C-A is Benign according to our data. Variant chr10-71821844-C-A is described in ClinVar as [Benign]. Clinvar id is 258812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0832 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSAP	NM_002778.4	c.909+32G>T		intron_variant		ENST00000394936.8	NP_002769.1
PSAP	NM_001042465.3	c.918+32G>T		intron_variant			NP_001035930.1
PSAP	NM_001042466.3	c.915+32G>T		intron_variant			NP_001035931.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSAP	ENST00000394936.8	c.909+32G>T		intron_variant		1	NM_002778.4	ENSP00000378394.3
PSAP	ENST00000633965.1	c.318+32G>T		intron_variant		5		ENSP00000488331.1
PSAP	ENST00000493143.1	n.330+32G>T		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0647 AC: 9844 AN: 152084 Hom.: 368 Cov.: 32

Gnomad AFR AF: 0.0394

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0467

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.00404

Gnomad SAS AF: 0.0837

Gnomad FIN AF: 0.0646

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0851

Gnomad OTH AF: 0.0694

GnomAD3 exomes AF: 0.0694 AC: 17361 AN: 250066 Hom.: 718 AF XY: 0.0734 AC XY: 9928 AN XY: 135238

Gnomad AFR exome AF: 0.0398

Gnomad AMR exome AF: 0.0349

Gnomad ASJ exome AF: 0.119

Gnomad EAS exome AF: 0.00321

Gnomad SAS exome AF: 0.0919

Gnomad FIN exome AF: 0.0657

Gnomad NFE exome AF: 0.0849

Gnomad OTH exome AF: 0.0760

GnomAD4 exome AF: 0.0756 AC: 110470 AN: 1461508 Hom.: 4645 Cov.: 32 AF XY: 0.0773 AC XY: 56219 AN XY: 727058

Gnomad4 AFR exome AF: 0.0384

Gnomad4 AMR exome AF: 0.0362

Gnomad4 ASJ exome AF: 0.121

Gnomad4 EAS exome AF: 0.00212

Gnomad4 SAS exome AF: 0.0928

Gnomad4 FIN exome AF: 0.0610

Gnomad4 NFE exome AF: 0.0792

Gnomad4 OTH exome AF: 0.0735

GnomAD4 genome AF: 0.0647 AC: 9844 AN: 152202 Hom.: 368 Cov.: 32 AF XY: 0.0638 AC XY: 4748 AN XY: 74412

Gnomad4 AFR AF: 0.0393

Gnomad4 AMR AF: 0.0467

Gnomad4 ASJ AF: 0.121

Gnomad4 EAS AF: 0.00405

Gnomad4 SAS AF: 0.0846

Gnomad4 FIN AF: 0.0646

Gnomad4 NFE AF: 0.0851

Gnomad4 OTH AF: 0.0687

Alfa AF: 0.0778 Hom.: 108

Bravo AF: 0.0598

Asia WGS AF: 0.0330 AC: 116 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	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Jul 10, 2021

- -

Krabbe disease due to saposin A deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Sphingolipid activator protein 1 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.60
DANN	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs41307569; hg19: chr10-73581601;