10-71816550-C-T

Variant names:

• chr10-71816550-C-T
• rs7869
• NM_002778.4:c.*891G>A

Variant summary

Our verdict is Benign. The variant received -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:8
• Conservation: PhyloP100: -0.873
• Publications: 24 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
PSAP	NM_002778.4	c.*891G>A		3_prime_UTR_variant	Exon 14 of 14	ENST00000394936.8	NP_002769.1
PSAP	NM_001042465.3	c.*891G>A		3_prime_UTR_variant	Exon 15 of 15		NP_001035930.1
PSAP	NM_001042466.3	c.*891G>A		3_prime_UTR_variant	Exon 15 of 15		NP_001035931.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSAP	ENST00000394936.8	c.*891G>A		3_prime_UTR_variant	Exon 14 of 14	1	NM_002778.4	ENSP00000378394.3

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

African (AFR) AF: 0.433 AC: 3310 AN: 7650

American (AMR) AF: 0.425 AC: 10451 AN: 24572

Ashkenazi Jewish (ASJ) AF: 0.242 AC: 2438 AN: 10094

East Asian (EAS) AF: 0.632 AC: 5348 AN: 8468

South Asian (SAS) AF: 0.251 AC: 14792 AN: 58886

European-Finnish (FIN) AF: 0.348 AC: 9315 AN: 26752

Middle Eastern (MID) AF: 0.185 AC: 494 AN: 2674

European-Non Finnish (NFE) AF: 0.275 AC: 38158 AN: 138884

Other (OTH) AF: 0.298 AC: 3839 AN: 12878

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

African (AFR) AF: 0.433 AC: 17959 AN: 41460

American (AMR) AF: 0.356 AC: 5438 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 823 AN: 3470

East Asian (EAS) AF: 0.616 AC: 3178 AN: 5156

South Asian (SAS) AF: 0.267 AC: 1288 AN: 4824

European-Finnish (FIN) AF: 0.350 AC: 3698 AN: 10558

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.273 AC: 18524 AN: 67972

Other (OTH) AF: 0.320 AC: 676 AN: 2114

Alfa AF: 0.313 Hom.: 3809

Bravo AF: 0.353

Asia WGS AF: 0.402 AC: 1398 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 14, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Gaucher disease due to saposin C deficiency Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hearing loss, autosomal recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa-deafness syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.46
DANN	Benign	0.53
PhyloP100		-0.87
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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