rs200319381

Variant names:

• chr10-71828111-A-C
• rs200319381
• NM_002778.4:c.623T>G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_002778.4(PSAP):​c.623T>G​(p.Ile208Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000122 in 1,614,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: PSAP NM_002778.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 6.36

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 -11 ACMG points.

• PM1: In a domain Saposin B-type 2 (size 81) in uniprot entity SAP_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_002778.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.02133137).
• BP6: Variant 10-71828111-A-C is Benign according to our data. Variant chr10-71828111-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 445595.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000126 (184/1461888) while in subpopulation AMR AF= 0.00405 (181/44724). AF 95% confidence interval is 0.00356. There are 0 homozygotes in gnomad4_exome. There are 79 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSAP	NM_002778.4	c.623T>G	p.Ile208Ser	missense_variant	Exon 6 of 14	ENST00000394936.8	NP_002769.1
PSAP	NM_001042465.3	c.623T>G	p.Ile208Ser	missense_variant	Exon 6 of 15		NP_001035930.1
PSAP	NM_001042466.3	c.623T>G	p.Ile208Ser	missense_variant	Exon 6 of 15		NP_001035931.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSAP	ENST00000394936.8	c.623T>G	p.Ile208Ser	missense_variant	Exon 6 of 14	1	NM_002778.4	ENSP00000378394.3
PSAP	ENST00000633965.1	c.23T>G	p.Ile8Ser	missense_variant	Exon 1 of 6	5		ENSP00000488331.1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000640 AC: 161 AN: 251496 Hom.: 0 AF XY: 0.000515 AC XY: 70 AN XY: 135922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00460

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000126 AC: 184 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.000109 AC XY: 79 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00405

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74454

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000190 Hom.: 0

Bravo AF: 0.000355

ExAC AF: 0.000560 AC: 68

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Mar 09, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 10, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The I208S variant in the PSAP gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The I208S variant is observed in 160/34420 (0.46%) alleles from individuals of Latino background, in the ExAC dataset, an individuals were reported to be homozygous (Lek et al., 2016). The I208S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret I208S as a variant of uncertain significance. -

Sphingolipid activator protein 1 deficiency Benign:1

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PSAP-related disorder Benign:1

Aug 05, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Metachromatic leukodystrophy Benign:1

Nov 11, 2019

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;D
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.79	T;T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.021	T;T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	1.7	L;.
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		0.46	P;.
Vest4		0.66
MVP		0.88
MPC		0.12
ClinPred		0.12	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.64
gMVP		0.68

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: rs200319381; hg19: chr10-73587868;