NM_002778.4:c.1350+5G>A

Variant names:

• chr10-71819460-C-T
• rs11000016
• NM_002778.4:c.1350+5G>A

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.1350+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 1,613,782 control chromosomes in the GnomAD database, including 29,039 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2223 hom., cov: 33)
  • Exomes 𝑓: 0.19 (26816 hom.)
• Consequence: PSAP NM_002778.4 splice_region, intron
• Scores: Splicing: ADA: 0.5971
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 0.130
• Publications: 11 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=-0.78).
• BP6: Variant 10-71819460-C-T is Benign according to our data. Variant chr10-71819460-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.237 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.1350+5G>A		splice_region intron	N/A	NP_002769.1	P07602-1
	PSAP	NM_001042465.3		c.1359+5G>A		splice_region intron	N/A	NP_001035930.1	P07602-3
	PSAP	NM_001042466.3		c.1356+5G>A		splice_region intron	N/A	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.1350+5G>A		splice_region intron	N/A	ENSP00000378394.3	P07602-1
	PSAP	ENST00000870508.1		c.1482+5G>A		splice_region intron	N/A	ENSP00000540567.1
	PSAP	ENST00000931479.1		c.1413+5G>A		splice_region intron	N/A	ENSP00000601538.1

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25436 AN: 152134 Hom.: 2223 Cov.: 33

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.248

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.225

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.168

GnomAD2 exomes AF: 0.174 AC: 43735 AN: 251246 AF XY: 0.173

Gnomad AFR exome AF: 0.123

Gnomad AMR exome AF: 0.120

Gnomad ASJ exome AF: 0.168

Gnomad EAS exome AF: 0.237

Gnomad FIN exome AF: 0.222

Gnomad NFE exome AF: 0.192

Gnomad OTH exome AF: 0.165

GnomAD4 exome AF: 0.189 AC: 275761 AN: 1461528 Hom.: 26816 Cov.: 38 AF XY: 0.186 AC XY: 135527 AN XY: 727092

African (AFR) AF: 0.124 AC: 4149 AN: 33476

American (AMR) AF: 0.123 AC: 5482 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 4460 AN: 26136

East Asian (EAS) AF: 0.275 AC: 10913 AN: 39698

South Asian (SAS) AF: 0.129 AC: 11162 AN: 86250

European-Finnish (FIN) AF: 0.221 AC: 11792 AN: 53244

Middle Eastern (MID) AF: 0.126 AC: 718 AN: 5716

European-Non Finnish (NFE) AF: 0.194 AC: 216130 AN: 1111908

Other (OTH) AF: 0.181 AC: 10955 AN: 60382

GnomAD4 genome AF: 0.167 AC: 25437 AN: 152254 Hom.: 2223 Cov.: 33 AF XY: 0.168 AC XY: 12514 AN XY: 74444

African (AFR) AF: 0.123 AC: 5125 AN: 41546

American (AMR) AF: 0.152 AC: 2322 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 592 AN: 3468

East Asian (EAS) AF: 0.248 AC: 1281 AN: 5166

South Asian (SAS) AF: 0.128 AC: 617 AN: 4832

European-Finnish (FIN) AF: 0.225 AC: 2388 AN: 10598

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.185 AC: 12603 AN: 68022

Other (OTH) AF: 0.166 AC: 351 AN: 2112

Alfa AF: 0.178 Hom.: 3965

Bravo AF: 0.160

Asia WGS AF: 0.138 AC: 481 AN: 3478

EpiCase AF: 0.179

EpiControl AF: 0.183

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	Sphingolipid activator protein 1 deficiency (3)
-	-	2	Combined PSAP deficiency (2)
-	-	2	Krabbe disease due to saposin A deficiency (2)
-	-	2	Metachromatic leukodystrophy (2)
-	-	1	Atypical Gaucher Disease (1)
-	-	1	Galactosylceramide beta-galactosidase deficiency (1)
-	-	1	Gaucher disease due to saposin C deficiency (1)
-	-	1	Hearing loss, autosomal recessive (1)
-	-	1	not specified (1)
-	-	1	Retinitis pigmentosa-deafness syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	11
DANN	Benign	0.73
PhyloP100		0.13
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.60
dbscSNV1_RF	Benign	0.41
Splicevardb		1.0
SpliceAI score (max)		0.020		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: rs11000016; hg19: chr10-73579217; COSMIC: COSV56468900; COSMIC: COSV56468900;