rs76455588

Variant names:

• chr10-71851231-T-C
• rs76455588
• NM_002778.4:c.-10A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002778.4(PSAP):​c.-10A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00267 in 1,551,020 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (23 hom., cov: 34)
  • Exomes 𝑓: 0.0018 (25 hom.)
• Consequence: PSAP NM_002778.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.62
• Publications: 3 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, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• Gaucher disease due to saposin C deficiency

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

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

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 10-71851231-T-C is Benign according to our data. Variant chr10-71851231-T-C is described in ClinVar as Benign. ClinVar VariationId is 258804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.011 (1677/152384) while in subpopulation AFR AF = 0.035 (1457/41596). AF 95% confidence interval is 0.0335. There are 23 homozygotes in GnomAd4. There are 831 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 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.-10A>G		5_prime_UTR	Exon 1 of 14	NP_002769.1	P07602-1
	PSAP	NM_001042465.3		c.-10A>G		5_prime_UTR	Exon 1 of 15	NP_001035930.1	P07602-3
	PSAP	NM_001042466.3		c.-10A>G		5_prime_UTR	Exon 1 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.-10A>G		5_prime_UTR	Exon 1 of 14	ENSP00000378394.3	P07602-1
	PSAP	ENST00000870508.1		c.-10A>G		5_prime_UTR	Exon 1 of 15	ENSP00000540567.1
	PSAP	ENST00000931479.1		c.-10A>G		5_prime_UTR	Exon 1 of 14	ENSP00000601538.1

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1660 AN: 152266 Hom.: 22 Cov.: 34

Gnomad AFR AF: 0.0347

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00680

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.00406 AC: 627 AN: 154466 AF XY: 0.00299

Gnomad AFR exome AF: 0.0385

Gnomad AMR exome AF: 0.00400

Gnomad ASJ exome AF: 0.0133

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000651

Gnomad NFE exome AF: 0.000917

Gnomad OTH exome AF: 0.00570

GnomAD4 exome AF: 0.00176 AC: 2462 AN: 1398636 Hom.: 25 Cov.: 31 AF XY: 0.00163 AC XY: 1122 AN XY: 689876

African (AFR) AF: 0.0338 AC: 1068 AN: 31584

American (AMR) AF: 0.00476 AC: 170 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.0134 AC: 338 AN: 25172

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

South Asian (SAS) AF: 0.000101 AC: 8 AN: 79232

European-Finnish (FIN) AF: 0.000103 AC: 5 AN: 48718

Middle Eastern (MID) AF: 0.00772 AC: 44 AN: 5696

European-Non Finnish (NFE) AF: 0.000497 AC: 536 AN: 1078818

Other (OTH) AF: 0.00505 AC: 293 AN: 57984

GnomAD4 genome AF: 0.0110 AC: 1677 AN: 152384 Hom.: 23 Cov.: 34 AF XY: 0.0112 AC XY: 831 AN XY: 74518

African (AFR) AF: 0.0350 AC: 1457 AN: 41596

American (AMR) AF: 0.00679 AC: 104 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000691 AC: 47 AN: 68038

Other (OTH) AF: 0.0128 AC: 27 AN: 2116

Alfa AF: 0.00905 Hom.: 7

Bravo AF: 0.0125

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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 specified (1)
-	-	1	Sphingolipid activator protein 1 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.4
DANN	Benign	0.63
PhyloP100		-1.6
PromoterAI		0.054	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	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: rs76455588; hg19: chr10-73610988;