10-71820222-G-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.1005+18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,599,214 control chromosomes in the GnomAD database, including 13,966 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1857 hom., cov: 32)

Exomes 𝑓: 0.11 ( 12109 hom. )

Consequence

PSAP
NM_002778.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -2.37

Publications

7 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, 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)

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=-0.83).

BP6

Variant 10-71820222-G-A is Benign according to our data. Variant chr10-71820222-G-A is described in ClinVar as Benign. ClinVar VariationId is 94084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.351 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
PSAP	NM_002778.4	MANE Select	c.1005+18C>T	intron	N/A	NP_002769.1
PSAP	NM_001042465.3		c.1014+18C>T	intron	N/A	NP_001035930.1
PSAP	NM_001042466.3		c.1011+18C>T	intron	N/A	NP_001035931.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
PSAP	ENST00000394936.8	TSL:1 MANE Select	c.1005+18C>T	intron	N/A	ENSP00000378394.3
PSAP	ENST00000633965.1	TSL:5	c.414+18C>T	intron	N/A	ENSP00000488331.1
PSAP	ENST00000493143.1	TSL:2	n.426+18C>T	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.140

AC:

21234

AN:

152018

Hom.:

1848

Cov.:

show subpopulations

Gnomad AFR

AF:

0.194

Gnomad AMI

AF:

0.0746

Gnomad AMR

AF:

0.189

Gnomad ASJ

AF:

0.0629

Gnomad EAS

AF:

0.365

Gnomad SAS

AF:

0.131

Gnomad FIN

AF:

0.127

Gnomad MID

AF:

0.0669

Gnomad NFE

AF:

0.0869

Gnomad OTH

AF:

0.125

GnomAD2 exomes

AF:

0.154

AC:

38663

AN:

251430

AF XY:

0.142

show subpopulations

Gnomad AFR exome

AF:

0.198

Gnomad AMR exome

AF:

0.317

Gnomad ASJ exome

AF:

0.0659

Gnomad EAS exome

AF:

0.383

Gnomad FIN exome

AF:

0.131

Gnomad NFE exome

AF:

0.0835

Gnomad OTH exome

AF:

0.131

GnomAD4 exome

AF:

0.110

AC:

159842

AN:

1447078

Hom.:

12109

Cov.:

AF XY:

0.108

AC XY:

78175

AN XY:

720890

show subpopulations

African (AFR)

AF:

0.198

AC:

6561

AN:

33142

American (AMR)

AF:

0.305

AC:

13637

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.0671

AC:

1746

AN:

26034

East Asian (EAS)

AF:

0.389

AC:

15426

AN:

39626

South Asian (SAS)

AF:

0.117

AC:

10025

AN:

85970

European-Finnish (FIN)

AF:

0.130

AC:

6937

AN:

53414

Middle Eastern (MID)

AF:

0.0573

AC:

328

AN:

5726

European-Non Finnish (NFE)

AF:

0.0891

AC:

97903

AN:

1098522

Other (OTH)

AF:

0.121

AC:

7279

AN:

59938

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

7250

14500

21750

29000

36250

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4088

8176

12264

16352

20440

<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:

0.140

AC:

21258

AN:

152136

Hom.:

1857

Cov.:

AF XY:

0.143

AC XY:

10613

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.194

AC:

8042

AN:

41474

American (AMR)

AF:

0.189

AC:

2892

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0629

AC:

218

AN:

3468

East Asian (EAS)

AF:

0.365

AC:

1880

AN:

5152

South Asian (SAS)

AF:

0.130

AC:

628

AN:

4818

European-Finnish (FIN)

AF:

0.127

AC:

1342

AN:

10594

Middle Eastern (MID)

AF:

0.0616

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0869

AC:

5907

AN:

68004

Other (OTH)

AF:

0.124

AC:

263

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

909

1819

2728

3638

4547

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

234

468

702

936

1170

<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:

0.103

Hom.:

355

Bravo

AF:

0.154

Asia WGS

AF:

0.251

AC:

872

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Oct 22, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 26, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sphingolipid activator protein 1 deficiency

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 10, 2021

Genome-Nilou Lab

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.17

(source)

DANN

Benign

0.45

PhyloP100

-2.4

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

Splicevardb

2.0

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

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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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over