chr10-71821844-C-A

Variant names:

• chr10-71821844-C-A
• rs41307569
• NM_002778.4:c.909+32G>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.909+32G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0746 in 1,613,710 control chromosomes in the GnomAD database, including 5,013 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (368 hom., cov: 32)
  • Exomes 𝑓: 0.076 (4645 hom.)
• Consequence: PSAP NM_002778.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.53
• Publications: 4 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=-0.85).
• BP6: Variant 10-71821844-C-A is Benign according to our data. Variant chr10-71821844-C-A is described in ClinVar as Benign. ClinVar VariationId is 258812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0832 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSAP	NM_002778.4	c.909+32G>T		intron_variant	Intron 8 of 13	ENST00000394936.8	NP_002769.1
PSAP	NM_001042465.3	c.918+32G>T		intron_variant	Intron 9 of 14		NP_001035930.1
PSAP	NM_001042466.3	c.915+32G>T		intron_variant	Intron 9 of 14		NP_001035931.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSAP	ENST00000394936.8	c.909+32G>T		intron_variant	Intron 8 of 13	1	NM_002778.4	ENSP00000378394.3
PSAP	ENST00000633965.1	c.318+32G>T		intron_variant	Intron 4 of 5	5		ENSP00000488331.1
PSAP	ENST00000493143.1	n.330+32G>T		intron_variant	Intron 1 of 2	2

Frequencies

GnomAD3 genomes AF: 0.0647 AC: 9844 AN: 152084 Hom.: 368 Cov.: 32

Gnomad AFR AF: 0.0394

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0467

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.00404

Gnomad SAS AF: 0.0837

Gnomad FIN AF: 0.0646

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0851

Gnomad OTH AF: 0.0694

GnomAD2 exomes AF: 0.0694 AC: 17361 AN: 250066 AF XY: 0.0734

Gnomad AFR exome AF: 0.0398

Gnomad AMR exome AF: 0.0349

Gnomad ASJ exome AF: 0.119

Gnomad EAS exome AF: 0.00321

Gnomad FIN exome AF: 0.0657

Gnomad NFE exome AF: 0.0849

Gnomad OTH exome AF: 0.0760

GnomAD4 exome AF: 0.0756 AC: 110470 AN: 1461508 Hom.: 4645 Cov.: 32 AF XY: 0.0773 AC XY: 56219 AN XY: 727058

African (AFR) AF: 0.0384 AC: 1285 AN: 33476

American (AMR) AF: 0.0362 AC: 1620 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 3159 AN: 26130

East Asian (EAS) AF: 0.00212 AC: 84 AN: 39696

South Asian (SAS) AF: 0.0928 AC: 8004 AN: 86234

European-Finnish (FIN) AF: 0.0610 AC: 3255 AN: 53400

Middle Eastern (MID) AF: 0.0926 AC: 534 AN: 5766

European-Non Finnish (NFE) AF: 0.0792 AC: 88092 AN: 1111718

Other (OTH) AF: 0.0735 AC: 4437 AN: 60384

GnomAD4 genome AF: 0.0647 AC: 9844 AN: 152202 Hom.: 368 Cov.: 32 AF XY: 0.0638 AC XY: 4748 AN XY: 74412

African (AFR) AF: 0.0393 AC: 1634 AN: 41532

American (AMR) AF: 0.0467 AC: 714 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 420 AN: 3470

East Asian (EAS) AF: 0.00405 AC: 21 AN: 5188

South Asian (SAS) AF: 0.0846 AC: 408 AN: 4822

European-Finnish (FIN) AF: 0.0646 AC: 685 AN: 10596

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0851 AC: 5784 AN: 67984

Other (OTH) AF: 0.0687 AC: 145 AN: 2112

Alfa AF: 0.0769 Hom.: 796

Bravo AF: 0.0598

Asia WGS AF: 0.0330 AC: 116 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

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

- -

Sphingolipid activator protein 1 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	-0.85
CADD	Benign	0.60
DANN	Benign	0.73
PhyloP100		-2.5
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)		0.11		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: rs41307569; hg19: chr10-73581601; COSMIC: COSV107501345; COSMIC: COSV107501345;