rs4747203

Variant names:

• chr10-71819125-T-C
• rs4747203
• NM_002778.4:c.1351-14A>G

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.1351-14A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.308 in 1,609,564 control chromosomes in the GnomAD database, including 81,465 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.34 (9632 hom., cov: 32)
  • Exomes 𝑓: 0.30 (71833 hom.)
• Consequence: PSAP NM_002778.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -0.532
• Publications: 17 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 10-71819125-T-C is Benign according to our data. Variant chr10-71819125-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.599 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.1351-14A>G		intron	N/A	NP_002769.1	P07602-1
	PSAP	NM_001042465.3		c.1360-14A>G		intron	N/A	NP_001035930.1	P07602-3
	PSAP	NM_001042466.3		c.1357-14A>G		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.1351-14A>G		intron	N/A	ENSP00000378394.3	P07602-1
	PSAP	ENST00000870508.1		c.1483-14A>G		intron	N/A	ENSP00000540567.1
	PSAP	ENST00000931479.1		c.1414-14A>G		intron	N/A	ENSP00000601538.1

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52311 AN: 151910 Hom.: 9609 Cov.: 32

Gnomad AFR AF: 0.440

Gnomad AMI AF: 0.263

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.617

Gnomad SAS AF: 0.279

Gnomad FIN AF: 0.353

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.327

GnomAD2 exomes AF: 0.341 AC: 85103 AN: 249526 AF XY: 0.326

Gnomad AFR exome AF: 0.450

Gnomad AMR exome AF: 0.445

Gnomad ASJ exome AF: 0.239

Gnomad EAS exome AF: 0.622

Gnomad FIN exome AF: 0.352

Gnomad NFE exome AF: 0.277

Gnomad OTH exome AF: 0.305

GnomAD4 exome AF: 0.304 AC: 443173 AN: 1457536 Hom.: 71833 Cov.: 33 AF XY: 0.300 AC XY: 217451 AN XY: 725230

African (AFR) AF: 0.449 AC: 14994 AN: 33390

American (AMR) AF: 0.436 AC: 19432 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.242 AC: 6322 AN: 26100

East Asian (EAS) AF: 0.665 AC: 26380 AN: 39664

South Asian (SAS) AF: 0.266 AC: 22899 AN: 86044

European-Finnish (FIN) AF: 0.351 AC: 18750 AN: 53348

Middle Eastern (MID) AF: 0.203 AC: 1166 AN: 5758

European-Non Finnish (NFE) AF: 0.284 AC: 314288 AN: 1108372

Other (OTH) AF: 0.314 AC: 18942 AN: 60244

GnomAD4 genome AF: 0.344 AC: 52371 AN: 152028 Hom.: 9632 Cov.: 32 AF XY: 0.348 AC XY: 25851 AN XY: 74290

African (AFR) AF: 0.441 AC: 18267 AN: 41436

American (AMR) AF: 0.358 AC: 5477 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 823 AN: 3468

East Asian (EAS) AF: 0.617 AC: 3188 AN: 5168

South Asian (SAS) AF: 0.278 AC: 1337 AN: 4812

European-Finnish (FIN) AF: 0.353 AC: 3733 AN: 10578

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.273 AC: 18569 AN: 67962

Other (OTH) AF: 0.324 AC: 684 AN: 2108

Alfa AF: 0.299 Hom.: 3275

Bravo AF: 0.356

Asia WGS AF: 0.413 AC: 1438 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	Sphingolipid activator protein 1 deficiency (3)
-	-	2	Combined PSAP deficiency (2)
-	-	2	Krabbe disease due to saposin A deficiency (2)
-	-	2	not specified (2)
-	-	1	Atypical Gaucher Disease (1)
-	-	1	CDH23-related disorder (1)
-	-	1	Galactosylceramide beta-galactosidase deficiency (1)
-	-	1	Gaucher disease due to saposin C deficiency (1)
-	-	1	Metachromatic leukodystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.75
DANN	Benign	0.73
PhyloP100		-0.53
BranchPoint Hunter		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4747203; hg19: chr10-73578882;