rs11000019

Positions:

• chr10-71831773-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.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

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=-0.93).
• BP6: Variant 10-71831773-G-A is Benign according to our data. Variant chr10-71831773-G-A is described in ClinVar as [Benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSAP	NM_002778.4	c.249+73C>T		intron_variant		ENST00000394936.8	NP_002769.1
PSAP	NM_001042465.3	c.249+73C>T		intron_variant			NP_001035930.1
PSAP	NM_001042466.3	c.249+73C>T		intron_variant			NP_001035931.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSAP	ENST00000394936.8	c.249+73C>T		intron_variant		1	NM_002778.4	ENSP00000378394	P1

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

Gnomad4 AFR exome AF: 0.107

Gnomad4 AMR exome AF: 0.00829

Gnomad4 ASJ exome AF: 0.000397

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000965

Gnomad4 FIN exome AF: 0.0000386

Gnomad4 NFE exome AF: 0.000876

Gnomad4 OTH exome AF: 0.00849

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

Gnomad4 AFR AF: 0.106

Gnomad4 AMR AF: 0.0102

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.00131

Gnomad4 OTH AF: 0.0251

Alfa AF: 0.0248 Hom.: 35

Bravo AF: 0.0357

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.031
DANN	Benign	0.79
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: rs11000019; hg19: chr10-73591530;