4-7433320-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001085382.2(PSAPL1):c.1560C>A(p.His520Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000798 in 1,253,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 8.0e-7 ( 0 hom. )

Consequence

PSAPL1
NM_001085382.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.06

Publications

0 publications found

Variant links:

Genes affected

PSAPL1 (HGNC:33131): (prosaposin like 1) This gene encodes a protein that is related to the glycoprotein prosaposin. Based on sequence similarity between the encoded protein and prosaposin, it is predicted that the encoded protein is a preproprotein that is proteolytically processed to generate multiple protein products. These predicted products include saposins A-like, B-like, C-like, and D-like, which may play a role in the lysosomal degradation of sphingolipids. [provided by RefSeq, Jul 2015]

PSAPL1 links:

SORCS2 (HGNC:16698): (sortilin related VPS10 domain containing receptor 2) This gene encodes one family member of vacuolar protein sorting 10 (VPS10) domain-containing receptor proteins. The VPS10 domain name comes from the yeast carboxypeptidase Y sorting receptor Vps10 protein. Members of this gene family are large with many exons but the CDS lengths are usually less than 3700 nt. Very large introns typically separate the exons encoding the VPS10 domain; the remaining exons are separated by much smaller-sized introns. These genes are strongly expressed in the central nervous system. [provided by RefSeq, Jul 2008]

SORCS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.051216185).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSAPL1	NM_001085382.2 link	c.1560C>A	p.His520Gln	missense_variant	Exon 1 of 1	ENST00000319098.7	NP_001078851.1	Q6NUJ1
SORCS2	NM_020777.3 link	c.548+36965G>T		intron_variant	Intron 2 of 26	ENST00000507866.6	NP_065828.2	Q96PQ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PSAPL1	ENST00000319098.7 link	c.1560C>A	p.His520Gln	missense_variant	Exon 1 of 1	6	NM_001085382.2	ENSP00000317445.4	Q6NUJ1
SORCS2	ENST00000507866.6 link	c.548+36965G>T		intron_variant	Intron 2 of 26	1	NM_020777.3	ENSP00000422185.2	Q96PQ0
SORCS2	ENST00000511199.1 link	n.163+36965G>T		intron_variant	Intron 2 of 5	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.98e-7

AC:

AN:

1253314

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

602804

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27304

American (AMR)

AF:

0.00

AC:

AN:

15016

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18028

East Asian (EAS)

AF:

0.00

AC:

AN:

32352

South Asian (SAS)

AF:

0.00

AC:

AN:

51366

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43800

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5096

European-Non Finnish (NFE)

AF:

9.91e-7

AC:

AN:

1008698

Other (OTH)

AF:

0.00

AC:

AN:

51654

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 11, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1560C>A (p.H520Q) alteration is located in exon 1 (coding exon 1) of the PSAPL1 gene. This alteration results from a C to A substitution at nucleotide position 1560, causing the histidine (H) at amino acid position 520 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.059

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.00033

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0039

LIST_S2

Benign

0.22

M_CAP

Benign

0.0053

MetaRNN

Benign

0.051

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

PhyloP100

-1.1

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.26

REVEL

Benign

0.040

Sift

Benign

0.16

Polyphen

0.0010

Vest4

0.086

MutPred

0.33

Gain of stability (P = 0.1235);

MVP

0.34

MPC

0.026

ClinPred

0.055

GERP RS

-4.2

Varity_R

0.031

gMVP

0.26

Mutation Taster

=96/4

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over