dbSNP rs769259446: SGPL1:p.Arg222Gln (chr10-70868394-G-A) – ACMG Classification: Pathogenic (14 pts)

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_003901.4(SGPL1):c.665G>A(p.Arg222Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

SGPL1
NM_003901.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5O:1

Conservation

PhyloP100: 9.53

Variant links:

Genes affected

SGPL1 (HGNC:10817): (sphingosine-1-phosphate lyase 1) Enables sphinganine-1-phosphate aldolase activity. Involved in apoptotic signaling pathway; fatty acid metabolic process; and sphingolipid metabolic process. Located in endoplasmic reticulum. Implicated in nephrotic syndrome type 14. [provided by Alliance of Genome Resources, Apr 2022]

SGPL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.974

PP5

Variant 10-70868394-G-A is Pathogenic according to our data. Variant chr10-70868394-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 430861.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGPL1	NM_003901.4 link	c.665G>A	p.Arg222Gln	missense_variant	Exon 8 of 15	ENST00000373202.8	NP_003892.2	O95470

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGPL1	ENST00000373202.8 link	c.665G>A	p.Arg222Gln	missense_variant	Exon 8 of 15	1	NM_003901.4	ENSP00000362298.3		O95470

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251154

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135760

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461494

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727066

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000936

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nephrotic syndrome 14

Pathogenic:3Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Aug 24, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Centogene AG - the Rare Disease Company

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 12, 2023

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Jul 01, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 430861). This variant has been observed in individual(s) with clinical features of SGPL1-related conditions (PMID: 28165343, 30517686, 31130284). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs769259446, ExAC 0.006%). This sequence change replaces arginine with glutamine at codon 222 of the SGPL1 protein (p.Arg222Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg222 amino acid residue in SGPL1. Other variant(s) that disrupt this residue have been observed in individuals with SGPL1-related conditions (PMID: 28165339), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this variant affects SGPL1 protein function (PMID: 28165343). -

Nephrotic syndrome

Pathogenic:1

Nov 10, 2017

Yale Center for Mendelian Genomics, Yale University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.93

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.041

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.067

MutationAssessor

Pathogenic

4.0

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.98

MutPred

0.85

Gain of methylation at K219 (P = 0.1049);

MVP

0.88

MPC

1.0

ClinPred

1.0

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.85

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over