10-71828091-T-G

Variant names:

• chr10-71828091-T-G
• rs121918107
• NM_002778.4:c.643A>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_002778.4(PSAP):​c.643A>C​(p.Asn215His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N215K) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PSAP NM_002778.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.35
• Publications: 10 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: Pathogenic. The variant received 18 ACMG points.

• PM1: In a chain Saposin-B-Val (size 79) in uniprot entity SAP_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_002778.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-71828089-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 857581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 10-71828091-T-G is Pathogenic according to our data. Variant chr10-71828091-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSAP	NM_002778.4	c.643A>C	p.Asn215His	missense_variant	Exon 6 of 14	ENST00000394936.8	NP_002769.1
PSAP	NM_001042465.3	c.643A>C	p.Asn215His	missense_variant	Exon 6 of 15		NP_001035930.1
PSAP	NM_001042466.3	c.643A>C	p.Asn215His	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.643A>C	p.Asn215His	missense_variant	Exon 6 of 14	1	NM_002778.4	ENSP00000378394.3
PSAP	ENST00000633965.1	c.43A>C	p.Asn15His	missense_variant	Exon 1 of 6	5		ENSP00000488331.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00110 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sphingolipid activator protein 1 deficiency Pathogenic:3

Jul 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 215 of the PSAP protein (p.Asn215His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with metachromatic leukodystrophy due to saposin B deficiency (PMID: 10682309). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13367). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PSAP protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PSAP function (PMID: 17561962). This variant disrupts the p.Asn215 amino acid residue in PSAP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10196694, 17616409, 18693274, 26462614). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

PSAP-related disorder Pathogenic:1

Nov 03, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PSAP c.643A>C variant is predicted to result in the amino acid substitution p.Asn215His. This variant was reported in the homozygous state an individual with metachromatic leukodystrophy (Wrobe et al 2000. PubMed ID: 10682309). In vitro functional studies show this variant results in an unglycosylated protein with strongly reduced activity (Remmel et al 2007. PubMed ID: 17561962). Another variant at the same position, p.Asn215Lys, has also been reported in the homozygous and compound heterozygous states in individuals with metachromatic leukodystrophy (Regis. 1999. PubMed ID: 10196694; Fenu. 2019. PubMed ID: 31289144). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Taken together, the p.Asn215His variant is interpreted as likely pathogenic. -

Metachromatic leukodystrophy Pathogenic:1

Mar 13, 2025

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Pathogenic	2.9	M;.
PhyloP100		7.4
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.89
MutPred		0.85		Loss of relative solvent accessibility (P = 0.114);Loss of relative solvent accessibility (P = 0.114);
MVP		0.89
MPC		0.29
ClinPred		0.99	D
GERP RS		5.6
PromoterAI		-0.034	Neutral
Varity_R		0.95
gMVP		0.74
Mutation Taster		=7/93	disease causing (ClinVar)

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: rs121918107; hg19: chr10-73587848;