rs4747202

Variant names:

• chr10-71817510-G-A
• rs4747202
• NM_002778.4:c.1540-34C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-71817510-G-A
• chr10-71817510-G-C

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.1540-34C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 1,610,128 control chromosomes in the GnomAD database, including 13,892 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: 33)
  • Exomes 𝑓: 0.11 (12035 hom.)
• Consequence: PSAP NM_002778.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0710
• Publications: 7 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=-0.82).
• BP6: Variant 10-71817510-G-A is Benign according to our data. Variant chr10-71817510-G-A is described in ClinVar as Benign. ClinVar VariationId is 258811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.353 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSAP	NM_002778.4	c.1540-34C>T		intron_variant	Intron 13 of 13	ENST00000394936.8	NP_002769.1
PSAP	NM_001042465.3	c.1549-34C>T		intron_variant	Intron 14 of 14		NP_001035930.1
PSAP	NM_001042466.3	c.1546-34C>T		intron_variant	Intron 14 of 14		NP_001035931.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSAP	ENST00000394936.8	c.1540-34C>T		intron_variant	Intron 13 of 13	1	NM_002778.4	ENSP00000378394.3

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21256 AN: 151992 Hom.: 1848 Cov.: 33

Gnomad AFR AF: 0.193

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.0629

Gnomad EAS AF: 0.367

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0868

Gnomad OTH AF: 0.124

GnomAD2 exomes AF: 0.154 AC: 38517 AN: 250870 AF XY: 0.141

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: 159703 AN: 1458018 Hom.: 12035 Cov.: 29 AF XY: 0.108 AC XY: 78030 AN XY: 725608

African (AFR) AF: 0.197 AC: 6563 AN: 33364

American (AMR) AF: 0.304 AC: 13615 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0669 AC: 1746 AN: 26116

East Asian (EAS) AF: 0.389 AC: 15435 AN: 39678

South Asian (SAS) AF: 0.114 AC: 9783 AN: 86176

European-Finnish (FIN) AF: 0.130 AC: 6921 AN: 53338

Middle Eastern (MID) AF: 0.0579 AC: 329 AN: 5686

European-Non Finnish (NFE) AF: 0.0884 AC: 98035 AN: 1108680

Other (OTH) AF: 0.121 AC: 7276 AN: 60258

GnomAD4 genome AF: 0.140 AC: 21280 AN: 152110 Hom.: 1857 Cov.: 33 AF XY: 0.143 AC XY: 10643 AN XY: 74382

African (AFR) AF: 0.193 AC: 8027 AN: 41494

American (AMR) AF: 0.189 AC: 2879 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0629 AC: 218 AN: 3468

East Asian (EAS) AF: 0.366 AC: 1895 AN: 5172

South Asian (SAS) AF: 0.128 AC: 616 AN: 4818

European-Finnish (FIN) AF: 0.127 AC: 1349 AN: 10594

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0868 AC: 5903 AN: 67974

Other (OTH) AF: 0.123 AC: 261 AN: 2114

Alfa AF: 0.113 Hom.: 558

Bravo AF: 0.154

Asia WGS AF: 0.250 AC: 867 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Combined PSAP deficiency Benign:1

Oct 25, 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

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sphingolipid activator protein 1 deficiency Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance: 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	-0.82
CADD	Benign	5.1
DANN	Benign	0.75
PhyloP100		0.071
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs4747202; hg19: chr10-73577267; COSMIC: COSV56453853; COSMIC: COSV56453853;