rs121918107
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_002778.4(PSAP):āc.643A>Cā(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 (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N215K) has been classified as Pathogenic.
Frequency
Consequence
NM_002778.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PSAP | NM_002778.4 | c.643A>C | p.Asn215His | missense_variant | 6/14 | ENST00000394936.8 | |
PSAP | NM_001042465.3 | c.643A>C | p.Asn215His | missense_variant | 6/15 | ||
PSAP | NM_001042466.3 | c.643A>C | p.Asn215His | missense_variant | 6/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PSAP | ENST00000394936.8 | c.643A>C | p.Asn215His | missense_variant | 6/14 | 1 | NM_002778.4 | P1 | |
PSAP | ENST00000633965.1 | c.46A>C | p.Asn16His | missense_variant | 1/6 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461890Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727246
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Sphingolipid activator protein 1 deficiency Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 29, 2023 | 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. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2007 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
PSAP-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 03, 2022 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at