rs11000019

Variant names:

• chr10-71831773-G-A
• rs11000019
• NM_002778.4:c.249+73C>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.249+73C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00676 in 1,445,678 control chromosomes in the GnomAD database, including 455 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (238 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (217 hom.)
• Consequence: PSAP NM_002778.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.74
• Publications: 9 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: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• Gaucher disease due to saposin C deficiency

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

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

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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=-0.93).
• BP6: Variant 10-71831773-G-A is Benign according to our data. Variant chr10-71831773-G-A is described in ClinVar as Benign. ClinVar VariationId is 1252398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSAP	NM_002778.4	MANE Select	c.249+73C>T		intron	N/A	NP_002769.1	P07602-1
	PSAP	NM_001042465.3		c.249+73C>T		intron	N/A	NP_001035930.1	P07602-3
	PSAP	NM_001042466.3		c.249+73C>T		intron	N/A	NP_001035931.1	P07602-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSAP	ENST00000394936.8	TSL:1 MANE Select	c.249+73C>T		intron	N/A	ENSP00000378394.3	P07602-1
	PSAP	ENST00000870508.1		c.249+73C>T		intron	N/A	ENSP00000540567.1
	PSAP	ENST00000931479.1		c.249+73C>T		intron	N/A	ENSP00000601538.1

Frequencies

GnomAD3 genomes AF: 0.0310 AC: 4706 AN: 151966 Hom.: 234 Cov.: 32

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00131

Gnomad OTH AF: 0.0253

GnomAD4 exome AF: 0.00391 AC: 5054 AN: 1293594 Hom.: 217 AF XY: 0.00345 AC XY: 2251 AN XY: 652140

African (AFR) AF: 0.107 AC: 3226 AN: 30038

American (AMR) AF: 0.00829 AC: 369 AN: 44512

Ashkenazi Jewish (ASJ) AF: 0.000397 AC: 10 AN: 25168

East Asian (EAS) AF: 0.00 AC: 0 AN: 38930

South Asian (SAS) AF: 0.000965 AC: 80 AN: 82874

European-Finnish (FIN) AF: 0.0000386 AC: 2 AN: 51768

Middle Eastern (MID) AF: 0.0142 AC: 60 AN: 4234

European-Non Finnish (NFE) AF: 0.000876 AC: 842 AN: 961296

Other (OTH) AF: 0.00849 AC: 465 AN: 54774

GnomAD4 genome AF: 0.0311 AC: 4724 AN: 152084 Hom.: 238 Cov.: 32 AF XY: 0.0291 AC XY: 2163 AN XY: 74342

African (AFR) AF: 0.106 AC: 4411 AN: 41454

American (AMR) AF: 0.0102 AC: 156 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

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

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4810

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10580

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.00131 AC: 89 AN: 68012

Other (OTH) AF: 0.0251 AC: 53 AN: 2114

Alfa AF: 0.0274 Hom.: 37

Bravo AF: 0.0357

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.031
DANN	Benign	0.79
PhyloP100		-2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs11000019; hg19: chr10-73591530;