rs3747860

Variant names:

• chr10-71819648-C-T
• rs3747860
• NM_002778.4:c.1193-26G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-71819648-C-T
• chr10-71819648-C-G

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.1193-26G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 1,613,892 control chromosomes in the GnomAD database, including 29,058 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2225 hom., cov: 32)
  • Exomes 𝑓: 0.19 (26833 hom.)
• Consequence: PSAP NM_002778.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.62
• Publications: 9 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=-0.84).
• BP6: Variant 10-71819648-C-T is Benign according to our data. Variant chr10-71819648-C-T is described in ClinVar as Benign. ClinVar VariationId is 258808.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.1193-26G>A		intron	N/A	NP_002769.1	P07602-1
	PSAP	NM_001042465.3		c.1202-26G>A		intron	N/A	NP_001035930.1	P07602-3
	PSAP	NM_001042466.3		c.1199-26G>A		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.1193-26G>A		intron	N/A	ENSP00000378394.3	P07602-1
	PSAP	ENST00000870508.1		c.1325-26G>A		intron	N/A	ENSP00000540567.1
	PSAP	ENST00000931479.1		c.1256-26G>A		intron	N/A	ENSP00000601538.1

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25442 AN: 152032 Hom.: 2225 Cov.: 32

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.248

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.225

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.169

GnomAD2 exomes AF: 0.174 AC: 43711 AN: 250966 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: 275872 AN: 1461740 Hom.: 26833 Cov.: 38 AF XY: 0.186 AC XY: 135561 AN XY: 727170

African (AFR) AF: 0.124 AC: 4156 AN: 33478

American (AMR) AF: 0.123 AC: 5481 AN: 44724

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

East Asian (EAS) AF: 0.275 AC: 10912 AN: 39700

South Asian (SAS) AF: 0.130 AC: 11171 AN: 86256

European-Finnish (FIN) AF: 0.221 AC: 11809 AN: 53330

Middle Eastern (MID) AF: 0.127 AC: 731 AN: 5768

European-Non Finnish (NFE) AF: 0.194 AC: 216189 AN: 1111954

Other (OTH) AF: 0.182 AC: 10963 AN: 60394

GnomAD4 genome AF: 0.167 AC: 25446 AN: 152152 Hom.: 2225 Cov.: 32 AF XY: 0.168 AC XY: 12520 AN XY: 74386

African (AFR) AF: 0.124 AC: 5143 AN: 41512

American (AMR) AF: 0.152 AC: 2317 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 592 AN: 3466

East Asian (EAS) AF: 0.248 AC: 1281 AN: 5158

South Asian (SAS) AF: 0.128 AC: 619 AN: 4830

European-Finnish (FIN) AF: 0.225 AC: 2388 AN: 10594

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

European-Non Finnish (NFE) AF: 0.185 AC: 12595 AN: 67982

Other (OTH) AF: 0.167 AC: 353 AN: 2112

Alfa AF: 0.109 Hom.: 250

Bravo AF: 0.160

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	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	-0.84
CADD	Benign	0.016
DANN	Benign	0.77
PhyloP100		-3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs3747860; hg19: chr10-73579405; COSMIC: COSV56446631; COSMIC: COSV56446631;