rs113284884

Variant names:

• chr10-71817319-G-C
• rs113284884
• NM_002778.4:c.*122C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002778.4(PSAP):​c.*122C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00664 in 1,053,852 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0056 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0068 (39 hom.)
• Consequence: PSAP NM_002778.4 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.429
• Publications: 1 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: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• Gaucher disease due to saposin C deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Krabbe disease due to saposin A deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• metachromatic leukodystrophy due to saposin B deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 10-71817319-G-C is Benign according to our data. Variant chr10-71817319-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 300503.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00564 (859/152338) while in subpopulation NFE AF = 0.00816 (555/68040). AF 95% confidence interval is 0.0076. There are 4 homozygotes in GnomAd4. There are 458 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,Unknown gene

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.*122C>G		3_prime_UTR	Exon 14 of 14	NP_002769.1	P07602-1
	PSAP	NM_001042465.3		c.*122C>G		3_prime_UTR	Exon 15 of 15	NP_001035930.1	P07602-3
	PSAP	NM_001042466.3		c.*122C>G		3_prime_UTR	Exon 15 of 15	NP_001035931.1	P07602-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSAP	ENST00000394936.8	TSL:1 MANE Select	c.*122C>G		3_prime_UTR	Exon 14 of 14	ENSP00000378394.3	P07602-1
	PSAP	ENST00000870508.1		c.*122C>G		3_prime_UTR	Exon 15 of 15	ENSP00000540567.1
	PSAP	ENST00000931479.1		c.*122C>G		3_prime_UTR	Exon 14 of 14	ENSP00000601538.1

Frequencies

GnomAD3 genomes AF: 0.00565 AC: 860 AN: 152220 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.0137

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00816

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.00681 AC: 6141 AN: 901514 Hom.: 39 Cov.: 13 AF XY: 0.00679 AC XY: 3204 AN XY: 471858

African (AFR) AF: 0.00137 AC: 31 AN: 22658

American (AMR) AF: 0.00246 AC: 108 AN: 43980

Ashkenazi Jewish (ASJ) AF: 0.00194 AC: 44 AN: 22692

East Asian (EAS) AF: 0.00 AC: 0 AN: 37226

South Asian (SAS) AF: 0.00463 AC: 347 AN: 74978

European-Finnish (FIN) AF: 0.0125 AC: 597 AN: 47582

Middle Eastern (MID) AF: 0.00127 AC: 6 AN: 4728

European-Non Finnish (NFE) AF: 0.00778 AC: 4709 AN: 605348

Other (OTH) AF: 0.00706 AC: 299 AN: 42322

GnomAD4 genome AF: 0.00564 AC: 859 AN: 152338 Hom.: 4 Cov.: 33 AF XY: 0.00615 AC XY: 458 AN XY: 74482

African (AFR) AF: 0.00120 AC: 50 AN: 41578

American (AMR) AF: 0.00503 AC: 77 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00414 AC: 20 AN: 4826

European-Finnish (FIN) AF: 0.0137 AC: 145 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00816 AC: 555 AN: 68040

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00789 Hom.: 1

Bravo AF: 0.00476

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Combined PSAP deficiency (1)
-	-	1	Gaucher disease due to saposin C deficiency (1)
-	-	1	Krabbe disease due to saposin A deficiency (1)
-	-	1	not provided (1)
-	1	-	Sphingolipid activator protein 1 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.8
DANN	Benign	0.41
PhyloP100		0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Mutation Taster		=100/0	polymorphism

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: rs113284884; hg19: chr10-73577076;