Genetic Variant SPPL2A:p.Val518Val (chr15-50707809-G-C) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_032802.4(SPPL2A):c.1554C>G(p.Val518Val) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.104

Variant links:

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]

SPPL2A links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 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_multiple_submitters_no_conflicts, 2 stars. Variant chr15-50707809-G-C is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.104 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPPL2A	NM_032802.4 link	c.1554C>G	p.Val518Val	synonymous_variant	Exon 15 of 15	ENST00000261854.10	NP_116191.2	Q8TCT8
SPPL2A	XM_005254722.4 link	c.1608C>G	p.Val536Val	synonymous_variant	Exon 16 of 16		XP_005254779.1
SPPL2A	XM_017022680.2 link	c.*34C>G		3_prime_UTR_variant	Exon 15 of 15		XP_016878169.1
SPPL2A	XM_017022681.2 link	c.*34C>G		3_prime_UTR_variant	Exon 14 of 14		XP_016878170.1	A0A8V8TLZ2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPPL2A	ENST00000261854.10 link	c.1554C>G	p.Val518Val	synonymous_variant	Exon 15 of 15	1	NM_032802.4	ENSP00000261854.5		Q8TCT8

Frequencies

GnomAD3 genomes

AF:

0.00139

AC:

212

AN:

152116

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00111

AC XY:

150

AN XY:

135632

show subpopulations

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.:

Cov.:

AF XY:

0.00194

AC XY:

1347

AN XY:

693854

show subpopulations

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.:

Cov.:

AF XY:

0.00107

AC XY:

AN XY:

74426

show subpopulations

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.:

Bravo

AF:

0.00140

EpiCase

AF:

0.00170

EpiControl

AF:

0.00178

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

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