rs728289

Positions:

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

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSAP	NM_002778.4	c.41-3698T>C		intron_variant		ENST00000394936.8	NP_002769.1
PSAP	NM_001042465.3	c.41-3698T>C		intron_variant			NP_001035930.1
PSAP	NM_001042466.3	c.41-3698T>C		intron_variant			NP_001035931.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSAP	ENST00000394936.8	c.41-3698T>C		intron_variant		1	NM_002778.4	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

Gnomad4 AFR AF: 0.332

Gnomad4 AMR AF: 0.428

Gnomad4 ASJ AF: 0.584

Gnomad4 EAS AF: 0.221

Gnomad4 SAS AF: 0.523

Gnomad4 FIN AF: 0.524

Gnomad4 NFE AF: 0.552

Gnomad4 OTH AF: 0.493

Alfa AF: 0.535 Hom.: 36738

Bravo AF: 0.448

Asia WGS AF: 0.380 AC: 1327 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.5
DANN	Benign	0.36

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: rs728289; hg19: chr10-73597960;