10-70844506-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003901.4(SGPL1):c.61G>T(p.Val21Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,613,196 control chromosomes in the GnomAD database, including 12,514 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.093 (865 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11649 hom.)
• Consequence: SGPL1 NM_003901.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.93

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014781952).
• BP6: Variant 10-70844506-G-T is Benign according to our data. Variant chr10-70844506-G-T is described in ClinVar as [Benign]. Clinvar id is 1232847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-70844506-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SGPL1	NM_003901.4	c.61G>T	p.Val21Leu	missense_variant	3/15	ENST00000373202.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SGPL1	ENST00000373202.8	c.61G>T	p.Val21Leu	missense_variant	3/15	1	NM_003901.4	P1

Frequencies

GnomAD3 genomes AF: 0.0935 AC: 14226 AN: 152102 Hom.: 865 Cov.: 32

Gnomad AFR AF: 0.0374

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.0838

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0259

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.0967

GnomAD3 exomes AF: 0.0915 AC: 22995 AN: 251240 Hom.: 1379 AF XY: 0.0909 AC XY: 12342 AN XY: 135778

Gnomad AFR exome AF: 0.0366

Gnomad AMR exome AF: 0.0616

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0256

Gnomad FIN exome AF: 0.118

Gnomad NFE exome AF: 0.133

Gnomad OTH exome AF: 0.108

GnomAD4 exome AF: 0.119 AC: 173719 AN: 1460976 Hom.: 11649 Cov.: 31 AF XY: 0.116 AC XY: 84637 AN XY: 726846

Gnomad4 AFR exome AF: 0.0353

Gnomad4 AMR exome AF: 0.0655

Gnomad4 ASJ exome AF: 0.110

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0284

Gnomad4 FIN exome AF: 0.120

Gnomad4 NFE exome AF: 0.136

Gnomad4 OTH exome AF: 0.107

GnomAD4 genome AF: 0.0934 AC: 14222 AN: 152220 Hom.: 865 Cov.: 32 AF XY: 0.0893 AC XY: 6648 AN XY: 74418

Gnomad4 AFR AF: 0.0373

Gnomad4 AMR AF: 0.0838

Gnomad4 ASJ AF: 0.121

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0253

Gnomad4 FIN AF: 0.117

Gnomad4 NFE AF: 0.136

Gnomad4 OTH AF: 0.0956

Alfa AF: 0.124 Hom.: 2417

Bravo AF: 0.0894

TwinsUK AF: 0.154 AC: 572

ALSPAC AF: 0.148 AC: 571

ESP6500AA AF: 0.0388 AC: 171

ESP6500EA AF: 0.138 AC: 1186

ExAC AF: 0.0918 AC: 11146

Asia WGS AF: 0.0180 AC: 64 AN: 3478

EpiCase AF: 0.133

EpiControl AF: 0.126

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 05, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Nephrotic syndrome 14 Benign:1

Benign, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jun 24, 2022

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as benign. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with nephrotic syndrome, type 14 (MIM#617575). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to leucine. (I) 0251 - This variant is heterozygous. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of nephrotic syndrome (gnomAD v2: 22998 heterozygotes, 1586 homozygotes). (SB) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0805 - This variant has strong previous evidence of being benign in unrelated individuals. This variant has been classified multiple times as benign (ClinVar, LOVD). (SB) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.29	T;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.058
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.76	T;T
MetaRNN	Benign	0.0015	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.060	N;N
REVEL	Benign	0.052
Sift	Benign	0.43	T;T
Sift4G	Benign	0.65	T;T
Polyphen		0.0	B;.
Vest4		0.064
MutPred		0.10		Loss of ubiquitination at K25 (P = 0.1016);.;
MPC		0.27
ClinPred		0.0057	T
GERP RS		5.0
Varity_R		0.026
gMVP		0.74

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: rs12770335; hg19: chr10-72604263;