chr10-71821844-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -2.53

Publications

4 publications found

Variant links:

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, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
Gaucher disease due to saposin C deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, ClinGen
Krabbe disease due to saposin A deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, G2P
metachromatic leukodystrophy due to saposin B deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
Parkinson disease 24, autosomal dominant, susceptibility to
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

PSAP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PSAP	NM_002778.4	MANE Select	c.909+32G>T	intron	N/A	NP_002769.1	P07602-1
PSAP	NM_001042465.3		c.918+32G>T	intron	N/A	NP_001035930.1	P07602-3
PSAP	NM_001042466.3		c.915+32G>T	intron	N/A	NP_001035931.1	P07602-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PSAP	ENST00000394936.8	TSL:1 MANE Select	c.909+32G>T	intron	N/A	ENSP00000378394.3	P07602-1
PSAP	ENST00000870508.1		c.1041+32G>T	intron	N/A	ENSP00000540567.1
PSAP	ENST00000931479.1		c.972+32G>T	intron	N/A	ENSP00000601538.1

Frequencies

GnomAD3 genomes

AF:

0.0647

AC:

9844

AN:

152084

Hom.:

368

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0773

AC XY:

56219

AN XY:

727058

show subpopulations

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:

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

5585

11170

16756

22341

27926

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3060

6120

9180

12240

15300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0647

AC:

9844

AN:

152202

Hom.:

368

Cov.:

AF XY:

0.0638

AC XY:

4748

AN XY:

74412

show subpopulations

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:

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.0851

AC:

5784

AN:

67984

Other (OTH)

AF:

0.0687

AC:

145

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

461

922

1384

1845

2306

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

122

244

366

488

610

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0769

Hom.:

796

Bravo

AF:

0.0598

Asia WGS

AF:

0.0330

AC:

116

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Combined PSAP deficiency (1)

Krabbe disease due to saposin A deficiency (1)

not specified (1)

Sphingolipid activator protein 1 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.60

(source)

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)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over