chr10-71817319-G-C

Variant names:

• chr10-71817319-G-C
• rs113284884
• NM_002778.4:c.*122C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002778.4(PSAP):​c.*122C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00664 in 1,053,852 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0056 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0068 (39 hom.)
• Consequence: PSAP NM_002778.4 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.429
• Publications: 1 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 10-71817319-G-C is Benign according to our data. Variant chr10-71817319-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 300503.We mark this variant Benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, Likely_benign=3}.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00564 (859/152338) while in subpopulation NFE AF = 0.00816 (555/68040). AF 95% confidence interval is 0.0076. There are 4 homozygotes in GnomAd4. There are 458 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSAP	NM_002778.4	c.*122C>G		3_prime_UTR_variant	Exon 14 of 14	ENST00000394936.8	NP_002769.1
PSAP	NM_001042465.3	c.*122C>G		3_prime_UTR_variant	Exon 15 of 15		NP_001035930.1
PSAP	NM_001042466.3	c.*122C>G		3_prime_UTR_variant	Exon 15 of 15		NP_001035931.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSAP	ENST00000394936.8	c.*122C>G		3_prime_UTR_variant	Exon 14 of 14	1	NM_002778.4	ENSP00000378394.3

Frequencies

GnomAD3 genomes AF: 0.00565 AC: 860 AN: 152220 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.0137

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00816

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.00681 AC: 6141 AN: 901514 Hom.: 39 Cov.: 13 AF XY: 0.00679 AC XY: 3204 AN XY: 471858

African (AFR) AF: 0.00137 AC: 31 AN: 22658

American (AMR) AF: 0.00246 AC: 108 AN: 43980

Ashkenazi Jewish (ASJ) AF: 0.00194 AC: 44 AN: 22692

East Asian (EAS) AF: 0.00 AC: 0 AN: 37226

South Asian (SAS) AF: 0.00463 AC: 347 AN: 74978

European-Finnish (FIN) AF: 0.0125 AC: 597 AN: 47582

Middle Eastern (MID) AF: 0.00127 AC: 6 AN: 4728

European-Non Finnish (NFE) AF: 0.00778 AC: 4709 AN: 605348

Other (OTH) AF: 0.00706 AC: 299 AN: 42322

GnomAD4 genome AF: 0.00564 AC: 859 AN: 152338 Hom.: 4 Cov.: 33 AF XY: 0.00615 AC XY: 458 AN XY: 74482

African (AFR) AF: 0.00120 AC: 50 AN: 41578

American (AMR) AF: 0.00503 AC: 77 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00414 AC: 20 AN: 4826

European-Finnish (FIN) AF: 0.0137 AC: 145 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00816 AC: 555 AN: 68040

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00789 Hom.: 1

Bravo AF: 0.00476

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Sphingolipid activator protein 1 deficiency Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Gaucher disease due to saposin C deficiency Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Combined PSAP deficiency Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Krabbe disease due to saposin A deficiency Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1

Jul 09, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.8
DANN	Benign	0.41
PhyloP100		0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
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: rs113284884; hg19: chr10-73577076;