chr4-7433319-C-G

Variant names:

• chr4-7433319-C-G
• rs1056786507
• NM_001085382.2:c.1561G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001085382.2(PSAPL1):​c.1561G>C​(p.Ala521Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000284 in 1,406,170 control chromosomes in the GnomAD database, including 1 homozygotes. 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. A521T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000024 (1 hom.)
• Consequence: PSAPL1 NM_001085382.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0890
• 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_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=0.039288282).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSAPL1	NM_001085382.2	c.1561G>C	p.Ala521Pro	missense_variant	Exon 1 of 1	ENST00000319098.7	NP_001078851.1
SORCS2	NM_020777.3	c.548+36964C>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.1561G>C	p.Ala521Pro	missense_variant	Exon 1 of 1	6	NM_001085382.2	ENSP00000317445.4
SORCS2	ENST00000507866.6	c.548+36964C>G		intron_variant	Intron 2 of 26	1	NM_020777.3	ENSP00000422185.2
SORCS2	ENST00000511199.1	n.163+36964C>G		intron_variant	Intron 2 of 5	4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152226 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: 0.00000239 AC: 3 AN: 1253944 Hom.: 1 Cov.: 54 AF XY: 0.00000497 AC XY: 3 AN XY: 603066

African (AFR) AF: 0.00 AC: 0 AN: 27300

American (AMR) AF: 0.00 AC: 0 AN: 15058

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18044

East Asian (EAS) AF: 0.00 AC: 0 AN: 32404

South Asian (SAS) AF: 0.00 AC: 0 AN: 51564

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43828

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5098

European-Non Finnish (NFE) AF: 0.00000297 AC: 3 AN: 1008952

Other (OTH) AF: 0.00 AC: 0 AN: 51696

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74356

African (AFR) AF: 0.00 AC: 0 AN: 41462

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

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

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	Benign	0.12
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.00034	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0043	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.2	N
PhyloP100		0.089
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.070	N
REVEL	Benign	0.075
Sift	Pathogenic	0.0	D
Polyphen		0.0010	B
Vest4		0.039
MVP		0.072
MPC		0.22
ClinPred		0.18	T
GERP RS		0.82
Varity_R		0.10
gMVP		0.42
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: rs1056786507; hg19: chr4-7435046;