rs11000016

chr10-71819460-C-T

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.1350+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 1,613,782 control chromosomes in the GnomAD database, including 29,039 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2223 hom., cov: 33)
  • Exomes 𝑓: 0.19 (26816 hom.)
• Consequence: PSAP NM_002778.4 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.5971
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 0.130

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=-0.78).
• BP6: Variant 10-71819460-C-T is Benign according to our data. Variant chr10-71819460-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 258809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.237 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSAP	NM_002778.4	c.1350+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000394936.8
PSAP	NM_001042465.3	c.1359+5G>A		splice_donor_5th_base_variant, intron_variant
PSAP	NM_001042466.3	c.1356+5G>A		splice_donor_5th_base_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSAP	ENST00000394936.8	c.1350+5G>A		splice_donor_5th_base_variant, intron_variant		1	NM_002778.4	P1

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25436 AN: 152134 Hom.: 2223 Cov.: 33

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.248

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.225

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.168

GnomAD3 exomes AF: 0.174 AC: 43735 AN: 251246 Hom.: 4064 AF XY: 0.173 AC XY: 23497 AN XY: 135832

Gnomad AFR exome AF: 0.123

Gnomad AMR exome AF: 0.120

Gnomad ASJ exome AF: 0.168

Gnomad EAS exome AF: 0.237

Gnomad SAS exome AF: 0.128

Gnomad FIN exome AF: 0.222

Gnomad NFE exome AF: 0.192

Gnomad OTH exome AF: 0.165

GnomAD4 exome AF: 0.189 AC: 275761 AN: 1461528 Hom.: 26816 Cov.: 38 AF XY: 0.186 AC XY: 135527 AN XY: 727092

Gnomad4 AFR exome AF: 0.124

Gnomad4 AMR exome AF: 0.123

Gnomad4 ASJ exome AF: 0.171

Gnomad4 EAS exome AF: 0.275

Gnomad4 SAS exome AF: 0.129

Gnomad4 FIN exome AF: 0.221

Gnomad4 NFE exome AF: 0.194

Gnomad4 OTH exome AF: 0.181

GnomAD4 genome AF: 0.167 AC: 25437 AN: 152254 Hom.: 2223 Cov.: 33 AF XY: 0.168 AC XY: 12514 AN XY: 74444

Gnomad4 AFR AF: 0.123

Gnomad4 AMR AF: 0.152

Gnomad4 ASJ AF: 0.171

Gnomad4 EAS AF: 0.248

Gnomad4 SAS AF: 0.128

Gnomad4 FIN AF: 0.225

Gnomad4 NFE AF: 0.185

Gnomad4 OTH AF: 0.166

Alfa AF: 0.180 Hom.: 3290

Bravo AF: 0.160

Asia WGS AF: 0.138 AC: 481 AN: 3478

EpiCase AF: 0.179

EpiControl AF: 0.183

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sphingolipid activator protein 1 deficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Combined PSAP deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Krabbe disease due to saposin A deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Metachromatic leukodystrophy Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 20, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Atypical Gaucher Disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Gaucher disease due to saposin C deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nonsyndromic Hearing Loss, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Galactosylceramide beta-galactosidase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Retinitis pigmentosa-deafness syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	11
Dann	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.60
dbscSNV1_RF	Benign	0.41
SpliceAI score (max)		0.020		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: rs11000016; hg19: chr10-73579217; COSMIC: COSV56468900; COSMIC: COSV56468900;