chr4-7433352-A-G

Variant names:

• chr4-7433352-A-G
• rs756186433
• NM_001085382.2:c.1528T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001085382.2(PSAPL1):​c.1528T>C​(p.Trp510Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000156 in 1,284,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: PSAPL1 NM_001085382.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.04
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSAPL1	NM_001085382.2	c.1528T>C	p.Trp510Arg	missense_variant	Exon 1 of 1	ENST00000319098.7	NP_001078851.1
SORCS2	NM_020777.3	c.548+36997A>G		intron_variant	Intron 2 of 26	ENST00000507866.6	NP_065828.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSAPL1	ENST00000319098.7	c.1528T>C	p.Trp510Arg	missense_variant	Exon 1 of 1	6	NM_001085382.2	ENSP00000317445.4
SORCS2	ENST00000507866.6	c.548+36997A>G		intron_variant	Intron 2 of 26	1	NM_020777.3	ENSP00000422185.2
SORCS2	ENST00000511199.1	n.163+36997A>G		intron_variant	Intron 2 of 5	4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000156 AC: 2 AN: 1284748 Hom.: 0 Cov.: 58 AF XY: 0.00000322 AC XY: 2 AN XY: 620780

African (AFR) AF: 0.00 AC: 0 AN: 28242

American (AMR) AF: 0.00 AC: 0 AN: 17736

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18508

East Asian (EAS) AF: 0.00 AC: 0 AN: 34052

South Asian (SAS) AF: 0.0000172 AC: 1 AN: 58288

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45708

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5156

European-Non Finnish (NFE) AF: 9.77e-7 AC: 1 AN: 1024018

Other (OTH) AF: 0.00 AC: 0 AN: 53040

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Benign	0.85
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.21	T
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.36	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		1.0
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-12	D
REVEL	Benign	0.29
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.14	B
Vest4		0.56
MutPred		0.87		Loss of catalytic residue at M513 (P = 0.0018);
MVP		0.62
MPC		0.13
ClinPred		1.0	D
GERP RS		0.51
Varity_R		0.61
gMVP		0.77
Mutation Taster		=95/5	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: rs756186433; hg19: chr4-7435079;