rs2070188

Positions:

• chr10-71851225-G-A
• chr10-71851225-G-C
• chr10-71851225-G-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.-4C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,550,292 control chromosomes in the GnomAD database, including 17,527 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1170 hom., cov: 34)
  • Exomes 𝑓: 0.15 (16357 hom.)
• Consequence: PSAP NM_002778.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.743

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=-0.76).
• BP6: Variant 10-71851225-G-A is Benign according to our data. Variant chr10-71851225-G-A is described in ClinVar as [Benign]. Clinvar id is 258806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.244 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSAP	NM_002778.4	c.-4C>T		5_prime_UTR_variant	1/14	ENST00000394936.8	NP_002769.1
PSAP	NM_001042465.3	c.-4C>T		5_prime_UTR_variant	1/15		NP_001035930.1
PSAP	NM_001042466.3	c.-4C>T		5_prime_UTR_variant	1/15		NP_001035931.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSAP	ENST00000394936.8	c.-4C>T		5_prime_UTR_variant	1/14	1	NM_002778.4	ENSP00000378394.3

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17768 AN: 152188 Hom.: 1167 Cov.: 34

Gnomad AFR AF: 0.0569

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.0889

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.256

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.120

GnomAD3 exomes AF: 0.128 AC: 19787 AN: 154448 Hom.: 1499 AF XY: 0.129 AC XY: 10540 AN XY: 81688

Gnomad AFR exome AF: 0.0570

Gnomad AMR exome AF: 0.0668

Gnomad ASJ exome AF: 0.103

Gnomad EAS exome AF: 0.248

Gnomad SAS exome AF: 0.109

Gnomad FIN exome AF: 0.114

Gnomad NFE exome AF: 0.156

Gnomad OTH exome AF: 0.126

GnomAD4 exome AF: 0.149 AC: 207747 AN: 1397984 Hom.: 16357 Cov.: 32 AF XY: 0.147 AC XY: 101679 AN XY: 689596

Gnomad4 AFR exome AF: 0.0541

Gnomad4 AMR exome AF: 0.0676

Gnomad4 ASJ exome AF: 0.103

Gnomad4 EAS exome AF: 0.296

Gnomad4 SAS exome AF: 0.110

Gnomad4 FIN exome AF: 0.117

Gnomad4 NFE exome AF: 0.155

Gnomad4 OTH exome AF: 0.140

GnomAD4 genome AF: 0.117 AC: 17764 AN: 152308 Hom.: 1170 Cov.: 34 AF XY: 0.116 AC XY: 8637 AN XY: 74468

Gnomad4 AFR AF: 0.0569

Gnomad4 AMR AF: 0.0888

Gnomad4 ASJ AF: 0.113

Gnomad4 EAS AF: 0.256

Gnomad4 SAS AF: 0.102

Gnomad4 FIN AF: 0.116

Gnomad4 NFE AF: 0.150

Gnomad4 OTH AF: 0.119

Alfa AF: 0.133 Hom.: 1693

Bravo AF: 0.111

Asia WGS AF: 0.127 AC: 443 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 22, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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	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. -

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. -

Sphingolipid activator protein 1 deficiency Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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. -

Metachromatic leukodystrophy Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 20, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	11
DANN	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
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

LitVar

Other links and lift over

dbSNP: rs2070188; hg19: chr10-73610982; COSMIC: COSV67550446;