10-71820198-G-C

Variant names:

• chr10-71820198-G-C
• rs111759923
• NM_002778.4:c.1005+42C>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.1005+42C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 1,534,274 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (17 hom.)
• Consequence: PSAP NM_002778.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.274
• Publications: 0 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, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)
• Gaucher disease due to saposin C deficiency

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

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

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), 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 10-71820198-G-C is Benign according to our data. Variant chr10-71820198-G-C is described in ClinVar as [Benign]. Clinvar id is 258807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00331 (504/152298) while in subpopulation SAS AF = 0.0108 (52/4826). AF 95% confidence interval is 0.00859. There are 3 homozygotes in GnomAd4. There are 247 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSAP	NM_002778.4	c.1005+42C>G		intron_variant	Intron 9 of 13	ENST00000394936.8	NP_002769.1
PSAP	NM_001042465.3	c.1014+42C>G		intron_variant	Intron 10 of 14		NP_001035930.1
PSAP	NM_001042466.3	c.1011+42C>G		intron_variant	Intron 10 of 14		NP_001035931.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSAP	ENST00000394936.8	c.1005+42C>G		intron_variant	Intron 9 of 13	1	NM_002778.4	ENSP00000378394.3
PSAP	ENST00000633965.1	c.414+42C>G		intron_variant	Intron 5 of 5	5		ENSP00000488331.1
PSAP	ENST00000493143.1	n.426+42C>G		intron_variant	Intron 2 of 2	2

Frequencies

GnomAD3 genomes AF: 0.00327 AC: 497 AN: 152180 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0112

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00257 AC: 647 AN: 251310 AF XY: 0.00283

Gnomad AFR exome AF: 0.00979

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000405

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00131 AC: 1804 AN: 1381976 Hom.: 17 Cov.: 25 AF XY: 0.00155 AC XY: 1076 AN XY: 692098

African (AFR) AF: 0.00924 AC: 293 AN: 31702

American (AMR) AF: 0.00137 AC: 61 AN: 44610

Ashkenazi Jewish (ASJ) AF: 0.00440 AC: 113 AN: 25666

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39276

South Asian (SAS) AF: 0.0103 AC: 870 AN: 84586

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00597 AC: 33 AN: 5530

European-Non Finnish (NFE) AF: 0.000301 AC: 313 AN: 1039498

Other (OTH) AF: 0.00208 AC: 120 AN: 57716

GnomAD4 genome AF: 0.00331 AC: 504 AN: 152298 Hom.: 3 Cov.: 32 AF XY: 0.00332 AC XY: 247 AN XY: 74478

African (AFR) AF: 0.00936 AC: 389 AN: 41560

American (AMR) AF: 0.00176 AC: 27 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.0108 AC: 52 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68018

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00145 Hom.: 0

Bravo AF: 0.00347

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.6
DANN	Benign	0.38
PhyloP100		0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs111759923; hg19: chr10-73579955;