rs121918110

chr10-71819860-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_002778.4(PSAP):c.1046T>C(p.Leu349Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L349L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PSAP NM_002778.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.22

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a disulfide_bond (size 73) in uniprot entity SAP_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_002778.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 10-71819860-A-G is Pathogenic according to our data. Variant chr10-71819860-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13372.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSAP	NM_002778.4	c.1046T>C	p.Leu349Pro	missense_variant	10/14	ENST00000394936.8
PSAP	NM_001042465.3	c.1055T>C	p.Leu352Pro	missense_variant	11/15
PSAP	NM_001042466.3	c.1052T>C	p.Leu351Pro	missense_variant	11/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSAP	ENST00000394936.8	c.1046T>C	p.Leu349Pro	missense_variant	10/14	1	NM_002778.4	P1
PSAP	ENST00000633965.1	c.458T>C	p.Leu153Pro	missense_variant	6/6	5
PSAP	ENST00000493143.1	n.467T>C		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Gaucher disease due to saposin C deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2007

- -

Metachromatic leukodystrophy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 09, 2023

Variant summary: PSAP c.1046T>C (p.Leu349Pro) results in a non-conservative amino acid change located in the Saposin-like type B, region 1 domain (IPR007856) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251204 control chromosomes. c.1046T>C has been reported in the literature in adult compound heterozygous individuals affected with Gaucher disease with saposin C deficiency, including two affected siblings from the same family (example: Tylki-Syzmanska_2007, DAmore_2021). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in ~50%-90% of normal activity, with results suggestive of a mild disease course (example: Motta_2014). The following publications have been ascertained in the context of this evaluation (PMID: 34649574, 24925315, 17919309, 20484222). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;D
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T;T
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-5.8	D;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.89
MutPred		0.93		Loss of stability (P = 0.0086);.;
MVP		0.97
MPC		0.35
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.96
gMVP		0.89

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: rs121918110; hg19: chr10-73579617;