rs1049882

Variant names:

• chr10-71819082-G-A
• rs1049882
• NM_002778.4:c.1380C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002778.4(PSAP):​c.1380C>T​(p.Pro460Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,614,108 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (17 hom.)
• Consequence: PSAP NM_002778.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -5.40
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 10-71819082-G-A is Benign according to our data. Variant chr10-71819082-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.4 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00296 (451/152294) while in subpopulation SAS AF = 0.0106 (51/4832). AF 95% confidence interval is 0.00825. There are 2 homozygotes in GnomAd4. There are 218 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002778.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSAP	NM_002778.4	MANE Select	c.1380C>T	p.Pro460Pro	synonymous	Exon 12 of 14	NP_002769.1
	PSAP	NM_001042465.3		c.1389C>T	p.Pro463Pro	synonymous	Exon 13 of 15	NP_001035930.1
	PSAP	NM_001042466.3		c.1386C>T	p.Pro462Pro	synonymous	Exon 13 of 15	NP_001035931.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSAP	ENST00000394936.8	TSL:1 MANE Select	c.1380C>T	p.Pro460Pro	synonymous	Exon 12 of 14	ENSP00000378394.3
	PSAP	ENST00000495196.1	TSL:2	n.190C>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.00293 AC: 446 AN: 152178 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00804

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0110

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00253 AC: 636 AN: 251180 AF XY: 0.00280

Gnomad AFR exome AF: 0.00882

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000440

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00130 AC: 1903 AN: 1461814 Hom.: 17 Cov.: 33 AF XY: 0.00155 AC XY: 1125 AN XY: 727194

African (AFR) AF: 0.00807 AC: 270 AN: 33476

American (AMR) AF: 0.00141 AC: 63 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00440 AC: 115 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0102 AC: 882 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00607 AC: 35 AN: 5766

European-Non Finnish (NFE) AF: 0.000366 AC: 407 AN: 1111962

Other (OTH) AF: 0.00209 AC: 126 AN: 60394

GnomAD4 genome AF: 0.00296 AC: 451 AN: 152294 Hom.: 2 Cov.: 32 AF XY: 0.00293 AC XY: 218 AN XY: 74470

African (AFR) AF: 0.00818 AC: 340 AN: 41542

American (AMR) AF: 0.00157 AC: 24 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.0106 AC: 51 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68028

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00211 Hom.: 1

Bravo AF: 0.00303

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.000593

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Sphingolipid activator protein 1 deficiency (2)
-	-	1	Combined PSAP deficiency (1)
-	-	1	Galactosylceramide beta-galactosidase deficiency (1)
-	-	1	Gaucher disease due to saposin C deficiency (1)
-	-	1	Krabbe disease due to saposin A deficiency (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.092
DANN	Benign	0.85
PhyloP100		-5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs1049882; hg19: chr10-73578839;