4-7433531-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001085382.2(PSAPL1):c.1349T>C(p.Ile450Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000269 in 1,609,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: PSAPL1 NM_001085382.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.02

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.025567412).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSAPL1	NM_001085382.2	c.1349T>C	p.Ile450Thr	missense_variant	1/1	ENST00000319098.7
SORCS2	NM_020777.3	c.548+37176A>G		intron_variant		ENST00000507866.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSAPL1	ENST00000319098.7	c.1349T>C	p.Ile450Thr	missense_variant	1/1		NM_001085382.2	P1
SORCS2	ENST00000507866.6	c.548+37176A>G		intron_variant		1	NM_020777.3	P1
SORCS2	ENST00000511199.1	n.163+37176A>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.000499 AC: 76 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000252 AC: 61 AN: 241586 Hom.: 0 AF XY: 0.000252 AC XY: 33 AN XY: 131158

Gnomad AFR exome AF: 0.0000676

Gnomad AMR exome AF: 0.000148

Gnomad ASJ exome AF: 0.00223

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000269

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000210

Gnomad OTH exome AF: 0.000339

GnomAD4 exome AF: 0.000245 AC: 357 AN: 1457388 Hom.: 0 Cov.: 63 AF XY: 0.000222 AC XY: 161 AN XY: 724744

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000339

Gnomad4 ASJ exome AF: 0.00276

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000292

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000172

Gnomad4 OTH exome AF: 0.000730

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.000497 AC XY: 37 AN XY: 74476

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00274

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000235 Hom.: 0

Bravo AF: 0.000824

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000238 AC: 1

ESP6500EA AF: 0.000712 AC: 6

ExAC AF: 0.000240 AC: 29

Asia WGS AF: 0.000289 AC: 1 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

Sep 01, 2021

The c.1349T>C (p.I450T) alteration is located in exon 1 (coding exon 1) of the PSAPL1 gene. This alteration results from a T to C substitution at nucleotide position 1349, causing the isoleucine (I) at amino acid position 450 to be replaced by a threonine (T). 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	0.20
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	18
Dann	Benign	0.97
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	0.93	N;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.23	B
Vest4		0.33
MVP		0.80
MPC		0.13
ClinPred		0.054	T
GERP RS		3.1
Varity_R		0.29
gMVP		0.25

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: rs201904662; hg19: chr4-7435258;