10-71816550-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.*891G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.316 in 442,896 control chromosomes in the GnomAD database, including 24,052 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9441 hom., cov: 33)
  • Exomes 𝑓: 0.30 (14611 hom.)
• Consequence: PSAP NM_002778.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.873

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=-0.8).
• BP6: Variant 10-71816550-C-T is Benign according to our data. Variant chr10-71816550-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 300498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.598 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSAP	NM_002778.4	c.*891G>A		3_prime_UTR_variant	14/14	ENST00000394936.8
PSAP	NM_001042465.3	c.*891G>A		3_prime_UTR_variant	15/15
PSAP	NM_001042466.3	c.*891G>A		3_prime_UTR_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSAP	ENST00000394936.8	c.*891G>A		3_prime_UTR_variant	14/14	1	NM_002778.4	P1

Frequencies

GnomAD3 genomes AF: 0.341 AC: 51826 AN: 151920 Hom.: 9422 Cov.: 33

Gnomad AFR AF: 0.433

Gnomad AMI AF: 0.266

Gnomad AMR AF: 0.356

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.616

Gnomad SAS AF: 0.268

Gnomad FIN AF: 0.350

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.322

GnomAD4 exome AF: 0.303 AC: 88145 AN: 290858 Hom.: 14611 Cov.: 0 AF XY: 0.293 AC XY: 47192 AN XY: 161112

Gnomad4 AFR exome AF: 0.433

Gnomad4 AMR exome AF: 0.425

Gnomad4 ASJ exome AF: 0.242

Gnomad4 EAS exome AF: 0.632

Gnomad4 SAS exome AF: 0.251

Gnomad4 FIN exome AF: 0.348

Gnomad4 NFE exome AF: 0.275

Gnomad4 OTH exome AF: 0.298

GnomAD4 genome AF: 0.341 AC: 51878 AN: 152038 Hom.: 9441 Cov.: 33 AF XY: 0.344 AC XY: 25594 AN XY: 74296

Gnomad4 AFR AF: 0.433

Gnomad4 AMR AF: 0.356

Gnomad4 ASJ AF: 0.237

Gnomad4 EAS AF: 0.616

Gnomad4 SAS AF: 0.267

Gnomad4 FIN AF: 0.350

Gnomad4 NFE AF: 0.273

Gnomad4 OTH AF: 0.320

Alfa AF: 0.314 Hom.: 3257

Bravo AF: 0.353

Asia WGS AF: 0.402 AC: 1398 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gaucher disease due to saposin C deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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

- -

Combined PSAP deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 14, 2021

- -

Krabbe disease due to saposin A deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

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	-0.80
Cadd	Benign	0.46
Dann	Benign	0.53
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1

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: rs7869; hg19: chr10-73576307; COSMIC: COSV56479425; COSMIC: COSV56479425;