15-50707809-G-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_032802.4(SPPL2A):c.1554C>G(p.Val518=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00197 in 1,538,102 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (3 hom.)
• Consequence: SPPL2A NM_032802.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -0.104

Genes affected

SPPL2A (HGNC:30227): (signal peptide peptidase like 2A) This gene encodes a member of the GXGD family of aspartic proteases, which are transmembrane proteins with two conserved catalytic motifs localized within the membrane-spanning regions, as well as a member of the signal peptide peptidase-like protease (SPPL) family. This protein is expressed in all major adult human tissues and localizes to late endosomal compartments and lysosomal membranes. A pseudogene of this gene also lies on chromosome 15. [provided by RefSeq, Feb 2012]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 15-50707809-G-C is Benign according to our data. Variant chr15-50707809-G-C is described in ClinVar as [Benign]. Clinvar id is 1165397.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-50707809-G-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.104 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPPL2A	NM_032802.4	c.1554C>G	p.Val518=	synonymous_variant	15/15	ENST00000261854.10
SPPL2A	XM_005254722.4	c.1608C>G	p.Val536=	synonymous_variant	16/16
SPPL2A	XM_017022680.2	c.*34C>G		3_prime_UTR_variant	15/15
SPPL2A	XM_017022681.2	c.*34C>G		3_prime_UTR_variant	14/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPPL2A	ENST00000261854.10	c.1554C>G	p.Val518=	synonymous_variant	15/15	1	NM_032802.4	P1

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 212 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00256

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00112 AC: 281 AN: 250926 Hom.: 0 AF XY: 0.00111 AC XY: 150 AN XY: 135632

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.000435

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00218

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00204 AC: 2823 AN: 1385868 Hom.: 3 Cov.: 23 AF XY: 0.00194 AC XY: 1347 AN XY: 693854

Gnomad4 AFR exome AF: 0.000468

Gnomad4 AMR exome AF: 0.000337

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000319

Gnomad4 NFE exome AF: 0.00260

Gnomad4 OTH exome AF: 0.00104

GnomAD4 genome AF: 0.00139 AC: 212 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.00107 AC XY: 80 AN XY: 74426

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00256

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00203 Hom.: 0

Bravo AF: 0.00140

EpiCase AF: 0.00170

EpiControl AF: 0.00178

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.40
Dann	Benign	0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs146593203; hg19: chr15-51000006;