4-7433405-C-T

Variant names:

• chr4-7433405-C-T
• rs764586181
• NM_001085382.2:c.1475G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001085382.2(PSAPL1):​c.1475G>A​(p.Ser492Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000464 in 1,507,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S492I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: PSAPL1 NM_001085382.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.429
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.094969034).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSAPL1	NM_001085382.2	c.1475G>A	p.Ser492Asn	missense_variant	Exon 1 of 1	ENST00000319098.7	NP_001078851.1
SORCS2	NM_020777.3	c.548+37050C>T		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.1475G>A	p.Ser492Asn	missense_variant	Exon 1 of 1	6	NM_001085382.2	ENSP00000317445.4
SORCS2	ENST00000507866.6	c.548+37050C>T		intron_variant	Intron 2 of 26	1	NM_020777.3	ENSP00000422185.2
SORCS2	ENST00000511199.1	n.163+37050C>T		intron_variant	Intron 2 of 5	4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000443 AC: 6 AN: 1354958 Hom.: 0 Cov.: 58 AF XY: 0.00 AC XY: 0 AN XY: 662990

African (AFR) AF: 0.00 AC: 0 AN: 30064

American (AMR) AF: 0.00 AC: 0 AN: 27330

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19948

East Asian (EAS) AF: 0.00 AC: 0 AN: 38110

South Asian (SAS) AF: 0.00 AC: 0 AN: 68350

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5306

European-Non Finnish (NFE) AF: 0.00000565 AC: 6 AN: 1061458

Other (OTH) AF: 0.00 AC: 0 AN: 55864

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74352

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.0000113

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	13
DANN	Benign	0.83
DEOGEN2	Benign	0.0021	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.095	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.66	N
PhyloP100		0.43
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	2.4	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	0.68	T
Polyphen		0.76	P
Vest4		0.31
MVP		0.54
MPC		0.21
ClinPred		0.18	T
GERP RS		1.2
Varity_R		0.056
gMVP		0.17
Mutation Taster		=100/0	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: rs764586181; hg19: chr4-7435132;