4-7433556-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001085382.2(PSAPL1):c.1324G>A(p.Val442Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000587 in 1,611,104 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00050 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00060 (2 hom.)
• Consequence: PSAPL1 NM_001085382.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.682

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]

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05408886).
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSAPL1	NM_001085382.2	c.1324G>A	p.Val442Ile	missense_variant	1/1	ENST00000319098.7
SORCS2	NM_020777.3	c.548+37201C>T		intron_variant		ENST00000507866.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSAPL1	ENST00000319098.7	c.1324G>A	p.Val442Ile	missense_variant	1/1		NM_001085382.2	P1
SORCS2	ENST00000507866.6	c.548+37201C>T		intron_variant		1	NM_020777.3	P1
SORCS2	ENST00000511199.1	n.163+37201C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.000480 AC: 73 AN: 152190 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000705

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000381 AC: 93 AN: 244138 Hom.: 1 AF XY: 0.000370 AC XY: 49 AN XY: 132548

Gnomad AFR exome AF: 0.000531

Gnomad AMR exome AF: 0.0000587

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000677

Gnomad SAS exome AF: 0.0000333

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000615

Gnomad OTH exome AF: 0.000336

GnomAD4 exome AF: 0.000596 AC: 869 AN: 1458796 Hom.: 2 Cov.: 63 AF XY: 0.000573 AC XY: 416 AN XY: 725548

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.0000450

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000328

Gnomad4 SAS exome AF: 0.000152

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000670

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152308 Hom.: 2 Cov.: 33 AF XY: 0.000389 AC XY: 29 AN XY: 74464

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000706

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000439 Hom.: 0

Bravo AF: 0.000468

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000234 AC: 1

ESP6500EA AF: 0.000472 AC: 4

ExAC AF: 0.000388 AC: 47

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2024

The c.1324G>A (p.V442I) alteration is located in exon 1 (coding exon 1) of the PSAPL1 gene. This alteration results from a G to A substitution at nucleotide position 1324, causing the valine (V) at amino acid position 442 to be replaced by an isoleucine (I). 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	0.10
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.036	T
Eigen	Benign	0.11
Eigen_PC	Benign	-0.062
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.054	T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.77	N
REVEL	Uncertain	0.41
Sift	Benign	0.071	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.14
MVP		0.97
MPC		0.20
ClinPred		0.022	T
GERP RS		3.4
Varity_R		0.077
gMVP		0.22

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

LitVar

Other links and lift over

dbSNP: rs199523405; hg19: chr4-7435283;