rs55829339

Variant names:

• chr10-71820222-G-A
• rs55829339
• NM_002778.4:c.1005+18C>T

Variant summary

Our verdict is Benign. The variant received -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:9
• Conservation: PhyloP100: -2.37
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• combined PSAP deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)
• Gaucher disease due to saposin C deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• Krabbe disease due to saposin A deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• metachromatic leukodystrophy due to saposin B deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• Parkinson disease 24, autosomal dominant, susceptibility to

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
PSAP	NM_002778.4	c.1005+18C>T		intron_variant	Intron 9 of 13	ENST00000394936.8	NP_002769.1
PSAP	NM_001042465.3	c.1014+18C>T		intron_variant	Intron 10 of 14		NP_001035930.1
PSAP	NM_001042466.3	c.1011+18C>T		intron_variant	Intron 10 of 14		NP_001035931.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSAP	ENST00000394936.8	c.1005+18C>T		intron_variant	Intron 9 of 13	1	NM_002778.4	ENSP00000378394.3
PSAP	ENST00000633965.1	c.414+18C>T		intron_variant	Intron 5 of 5	5		ENSP00000488331.1
PSAP	ENST00000493143.1	n.426+18C>T		intron_variant	Intron 2 of 2	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

GnomAD2 exomes AF: 0.154 AC: 38663 AN: 251430 AF XY: 0.142

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 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

African (AFR) AF: 0.198 AC: 6561 AN: 33142

American (AMR) AF: 0.305 AC: 13637 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0671 AC: 1746 AN: 26034

East Asian (EAS) AF: 0.389 AC: 15426 AN: 39626

South Asian (SAS) AF: 0.117 AC: 10025 AN: 85970

European-Finnish (FIN) AF: 0.130 AC: 6937 AN: 53414

Middle Eastern (MID) AF: 0.0573 AC: 328 AN: 5726

European-Non Finnish (NFE) AF: 0.0891 AC: 97903 AN: 1098522

Other (OTH) AF: 0.121 AC: 7279 AN: 59938

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

African (AFR) AF: 0.194 AC: 8042 AN: 41474

American (AMR) AF: 0.189 AC: 2892 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0629 AC: 218 AN: 3468

East Asian (EAS) AF: 0.365 AC: 1880 AN: 5152

South Asian (SAS) AF: 0.130 AC: 628 AN: 4818

European-Finnish (FIN) AF: 0.127 AC: 1342 AN: 10594

Middle Eastern (MID) AF: 0.0616 AC: 18 AN: 292

European-Non Finnish (NFE) AF: 0.0869 AC: 5907 AN: 68004

Other (OTH) AF: 0.124 AC: 263 AN: 2114

Alfa AF: 0.103 Hom.: 355

Bravo AF: 0.154

Asia WGS AF: 0.251 AC: 872 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 22, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 26, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sphingolipid activator protein 1 deficiency Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Combined PSAP deficiency Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Krabbe disease due to saposin A deficiency Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.17
DANN	Benign	0.45
PhyloP100		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs55829339; hg19: chr10-73579979; COSMIC: COSV56453858; COSMIC: COSV56453858;