10-71851221-T-A

Variant names:

• chr10-71851221-T-A
• rs121918106
• NM_002778.4:c.1A>T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_002778.4(PSAP):​c.1A>T​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000645 in 1,550,968 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 Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000064 (0 hom.)
• Consequence: PSAP NM_002778.4 initiator_codon
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.45
• Publications: 13 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 20 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 11 pathogenic variants. Next in-frame start position is after 76 codons. Genomic position: 71831869. Lost 0.143 part of the original CDS.
• PS1: Another start lost variant in NM_002778.4 (PSAP) was described as [Likely_pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-71851221-T-A is Pathogenic according to our data. Variant chr10-71851221-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 13365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002778.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSAP	NM_002778.4	MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 14	NP_002769.1
	PSAP	NM_001042465.3		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 15	NP_001035930.1
	PSAP	NM_001042466.3		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 15	NP_001035931.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSAP	ENST00000394936.8	TSL:1 MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 14	ENSP00000378394.3
	PSAP	ENST00000870508.1		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 15	ENSP00000540567.1
	PSAP	ENST00000931479.1		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 14	ENSP00000601538.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152258 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000129 AC: 2 AN: 154492 AF XY: 0.0000245

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000340

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000643 AC: 9 AN: 1398710 Hom.: 0 Cov.: 31 AF XY: 0.00000725 AC XY: 5 AN XY: 689912

African (AFR) AF: 0.00 AC: 0 AN: 31588

American (AMR) AF: 0.00 AC: 0 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25170

East Asian (EAS) AF: 0.00 AC: 0 AN: 35732

South Asian (SAS) AF: 0.00 AC: 0 AN: 79232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48792

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00000834 AC: 9 AN: 1078812

Other (OTH) AF: 0.00 AC: 0 AN: 57986

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152258 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74390

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41474

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Gaucher disease due to saposin C deficiency (2)
1	-	-	Combined PSAP deficiency (1)
1	-	-	Sphingolipid activator protein 1 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	18
DANN	Benign	0.85
DEOGEN2	Benign	0.23	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.58	T
PhyloP100		3.4
PROVEAN	Benign	-0.45	N
REVEL	Uncertain	0.41
Sift	Benign	0.091	T
Sift4G	Benign	0.79	T
Polyphen		0.70	P
Vest4		0.76
MutPred		0.91		Loss of solvent accessibility (P = 0.0152)
MVP		0.94
ClinPred		0.97	D
GERP RS		5.0
PromoterAI		-0.18	Neutral
Varity_R		0.68
gMVP		0.49
Mutation Taster		=6/194	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: rs121918106; hg19: chr10-73610978;