rs55829339

chr10-71820222-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.1005+18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,599,214 control chromosomes in the GnomAD database, including 13,966 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: 32)
  • Exomes 𝑓: 0.11 (12109 hom.)
• Consequence: PSAP NM_002778.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.37

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=-0.83).
• BP6: Variant 10-71820222-G-A is Benign according to our data. Variant chr10-71820222-G-A is described in ClinVar as [Benign]. Clinvar id is 94084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.351 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSAP	NM_002778.4	c.1005+18C>T		intron_variant		ENST00000394936.8
PSAP	NM_001042465.3	c.1014+18C>T		intron_variant
PSAP	NM_001042466.3	c.1011+18C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSAP	ENST00000394936.8	c.1005+18C>T		intron_variant		1	NM_002778.4	P1
PSAP	ENST00000633965.1	c.415+18C>T		intron_variant		5
PSAP	ENST00000493143.1	n.426+18C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21234 AN: 152018 Hom.: 1848 Cov.: 32

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.0629

Gnomad EAS AF: 0.365

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.0669

Gnomad NFE AF: 0.0869

Gnomad OTH AF: 0.125

GnomAD3 exomes AF: 0.154 AC: 38663 AN: 251430 Hom.: 4461 AF XY: 0.142 AC XY: 19247 AN XY: 135900

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: 0.118

Gnomad FIN exome AF: 0.131

Gnomad NFE exome AF: 0.0835

Gnomad OTH exome AF: 0.131

GnomAD4 exome AF: 0.110 AC: 159842 AN: 1447078 Hom.: 12109 Cov.: 31 AF XY: 0.108 AC XY: 78175 AN XY: 720890

Gnomad4 AFR exome AF: 0.198

Gnomad4 AMR exome AF: 0.305

Gnomad4 ASJ exome AF: 0.0671

Gnomad4 EAS exome AF: 0.389

Gnomad4 SAS exome AF: 0.117

Gnomad4 FIN exome AF: 0.130

Gnomad4 NFE exome AF: 0.0891

Gnomad4 OTH exome AF: 0.121

GnomAD4 genome AF: 0.140 AC: 21258 AN: 152136 Hom.: 1857 Cov.: 32 AF XY: 0.143 AC XY: 10613 AN XY: 74362

Gnomad4 AFR AF: 0.194

Gnomad4 AMR AF: 0.189

Gnomad4 ASJ AF: 0.0629

Gnomad4 EAS AF: 0.365

Gnomad4 SAS AF: 0.130

Gnomad4 FIN AF: 0.127

Gnomad4 NFE AF: 0.0869

Gnomad4 OTH AF: 0.124

Alfa AF: 0.104 Hom.: 193

Bravo AF: 0.154

Asia WGS AF: 0.251 AC: 872 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	-	- -

not provided Benign:2

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	- -

Sphingolipid activator protein 1 deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.17
Dann	Benign	0.45
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: rs55829339; hg19: chr10-73579979; COSMIC: COSV56453858; COSMIC: COSV56453858;