10-71851249-T-C

Variant names:

• chr10-71851249-T-C
• rs375720661
• NM_002778.4:c.-28A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002778.4(PSAP):​c.-28A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000222 in 1,397,964 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000022 (1 hom.)
• Consequence: PSAP NM_002778.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.45
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSAP	NM_002778.4	MANE Select	c.-28A>G		5_prime_UTR	Exon 1 of 14	NP_002769.1
	PSAP	NM_001042465.3		c.-28A>G		5_prime_UTR	Exon 1 of 15	NP_001035930.1
	PSAP	NM_001042466.3		c.-28A>G		5_prime_UTR	Exon 1 of 15	NP_001035931.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSAP	ENST00000394936.8	TSL:1 MANE Select	c.-28A>G		5_prime_UTR	Exon 1 of 14	ENSP00000378394.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000454 AC: 7 AN: 154290 AF XY: 0.0000734

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000222 AC: 31 AN: 1397964 Hom.: 1 Cov.: 31 AF XY: 0.0000363 AC XY: 25 AN XY: 689582

African (AFR) AF: 0.00 AC: 0 AN: 31582

American (AMR) AF: 0.00 AC: 0 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25162

East Asian (EAS) AF: 0.00 AC: 0 AN: 35728

South Asian (SAS) AF: 0.000278 AC: 22 AN: 79216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1078302

Other (OTH) AF: 0.000104 AC: 6 AN: 57956

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Benign	0.88
PhyloP100		3.4
PromoterAI		0.040	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=298/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs375720661; hg19: chr10-73611006;