rs728289

Variant names:

• chr10-71838203-A-G
• rs728289
• NM_002778.4:c.41-3698T>C

Your query was ambiguous. Multiple possible variants found:

• chr10-71838203-A-G
• chr10-71838203-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002778.4(PSAP):​c.41-3698T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 152,192 control chromosomes in the GnomAD database, including 17,319 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.47 (17319 hom., cov: 33)
• Consequence: PSAP NM_002778.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.430
• Publications: 5 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.547 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSAP	NM_002778.4	MANE Select	c.41-3698T>C		intron	N/A	NP_002769.1
	PSAP	NM_001042465.3		c.41-3698T>C		intron	N/A	NP_001035930.1
	PSAP	NM_001042466.3		c.41-3698T>C		intron	N/A	NP_001035931.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSAP	ENST00000394936.8	TSL:1 MANE Select	c.41-3698T>C		intron	N/A	ENSP00000378394.3

Frequencies

GnomAD3 genomes AF: 0.465 AC: 70782 AN: 152074 Hom.: 17306 Cov.: 33

Gnomad AFR AF: 0.332

Gnomad AMI AF: 0.580

Gnomad AMR AF: 0.428

Gnomad ASJ AF: 0.584

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.523

Gnomad FIN AF: 0.524

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.552

Gnomad OTH AF: 0.489

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.465 AC: 70815 AN: 152192 Hom.: 17319 Cov.: 33 AF XY: 0.463 AC XY: 34428 AN XY: 74410

African (AFR) AF: 0.332 AC: 13786 AN: 41522

American (AMR) AF: 0.428 AC: 6537 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.584 AC: 2029 AN: 3472

East Asian (EAS) AF: 0.221 AC: 1147 AN: 5180

South Asian (SAS) AF: 0.523 AC: 2524 AN: 4826

European-Finnish (FIN) AF: 0.524 AC: 5544 AN: 10580

Middle Eastern (MID) AF: 0.561 AC: 165 AN: 294

European-Non Finnish (NFE) AF: 0.552 AC: 37511 AN: 68000

Other (OTH) AF: 0.493 AC: 1043 AN: 2116

Alfa AF: 0.521 Hom.: 81195

Bravo AF: 0.448

Asia WGS AF: 0.380 AC: 1327 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.5
DANN	Benign	0.36
PhyloP100		0.43
Mutation Taster		=100/0	polymorphism (auto)

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: rs728289; hg19: chr10-73597960;