10-71851225-G-A

Variant names:

• chr10-71851225-G-A
• rs2070188
• NM_002778.4:c.-4C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002778.4(PSAP):​c.-4C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,550,292 control chromosomes in the GnomAD database, including 17,527 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1170 hom., cov: 34)
  • Exomes 𝑓: 0.15 (16357 hom.)
• Consequence: PSAP NM_002778.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.743
• Publications: 25 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 10-71851225-G-A is Benign according to our data. Variant chr10-71851225-G-A is described in ClinVar as Benign. ClinVar VariationId is 258806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.244 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSAP	NM_002778.4	MANE Select	c.-4C>T		5_prime_UTR	Exon 1 of 14	NP_002769.1	P07602-1
	PSAP	NM_001042465.3		c.-4C>T		5_prime_UTR	Exon 1 of 15	NP_001035930.1	P07602-3
	PSAP	NM_001042466.3		c.-4C>T		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.-4C>T		5_prime_UTR	Exon 1 of 14	ENSP00000378394.3	P07602-1
	PSAP	ENST00000870508.1		c.-4C>T		5_prime_UTR	Exon 1 of 15	ENSP00000540567.1
	PSAP	ENST00000931479.1		c.-4C>T		5_prime_UTR	Exon 1 of 14	ENSP00000601538.1

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17768 AN: 152188 Hom.: 1167 Cov.: 34

Gnomad AFR AF: 0.0569

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.0889

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.256

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.120

GnomAD2 exomes AF: 0.128 AC: 19787 AN: 154448 AF XY: 0.129

Gnomad AFR exome AF: 0.0570

Gnomad AMR exome AF: 0.0668

Gnomad ASJ exome AF: 0.103

Gnomad EAS exome AF: 0.248

Gnomad FIN exome AF: 0.114

Gnomad NFE exome AF: 0.156

Gnomad OTH exome AF: 0.126

GnomAD4 exome AF: 0.149 AC: 207747 AN: 1397984 Hom.: 16357 Cov.: 32 AF XY: 0.147 AC XY: 101679 AN XY: 689596

African (AFR) AF: 0.0541 AC: 1710 AN: 31582

American (AMR) AF: 0.0676 AC: 2412 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 2586 AN: 25170

East Asian (EAS) AF: 0.296 AC: 10560 AN: 35724

South Asian (SAS) AF: 0.110 AC: 8709 AN: 79214

European-Finnish (FIN) AF: 0.117 AC: 5683 AN: 48728

Middle Eastern (MID) AF: 0.132 AC: 750 AN: 5698

European-Non Finnish (NFE) AF: 0.155 AC: 167195 AN: 1078204

Other (OTH) AF: 0.140 AC: 8142 AN: 57964

GnomAD4 genome AF: 0.117 AC: 17764 AN: 152308 Hom.: 1170 Cov.: 34 AF XY: 0.116 AC XY: 8637 AN XY: 74468

African (AFR) AF: 0.0569 AC: 2365 AN: 41580

American (AMR) AF: 0.0888 AC: 1360 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 391 AN: 3470

East Asian (EAS) AF: 0.256 AC: 1321 AN: 5168

South Asian (SAS) AF: 0.102 AC: 495 AN: 4830

European-Finnish (FIN) AF: 0.116 AC: 1232 AN: 10618

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.150 AC: 10186 AN: 68008

Other (OTH) AF: 0.119 AC: 251 AN: 2116

Alfa AF: 0.132 Hom.: 1899

Bravo AF: 0.111

Asia WGS AF: 0.127 AC: 443 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Combined PSAP deficiency (2)
-	-	2	Krabbe disease due to saposin A deficiency (2)
-	-	2	Sphingolipid activator protein 1 deficiency (2)
-	-	1	Gaucher disease due to saposin C deficiency (1)
-	-	1	Metachromatic leukodystrophy (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	11
DANN	Benign	0.70
PhyloP100		0.74
PromoterAI		-0.13	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=300/0	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: rs2070188; hg19: chr10-73610982; COSMIC: COSV67550446;