15-50719990-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_032802.4(SPPL2A):​c.1438G>A​(p.Ala480Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

SPPL2A
NM_032802.4 missense

Scores

9
6
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.02
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.953

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SPPL2ANM_032802.4 linkc.1438G>A p.Ala480Thr missense_variant Exon 14 of 15 ENST00000261854.10 NP_116191.2 Q8TCT8
SPPL2AXM_005254722.4 linkc.1492G>A p.Ala498Thr missense_variant Exon 15 of 16 XP_005254779.1
SPPL2AXM_017022680.2 linkc.1381+2134G>A intron_variant Intron 14 of 14 XP_016878169.1
SPPL2AXM_017022681.2 linkc.1327+2134G>A intron_variant Intron 13 of 13 XP_016878170.1 A0A8V8TLZ2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SPPL2AENST00000261854.10 linkc.1438G>A p.Ala480Thr missense_variant Exon 14 of 15 1 NM_032802.4 ENSP00000261854.5 Q8TCT8

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Jul 04, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 480 of the SPPL2A protein (p.Ala480Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SPPL2A-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.17
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.13
T
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.82
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.91
D
M_CAP
Benign
0.084
D
MetaRNN
Pathogenic
0.95
D
MetaSVM
Benign
-0.63
T
MutationAssessor
Pathogenic
3.5
H
PrimateAI
Uncertain
0.49
T
PROVEAN
Uncertain
-3.8
D
REVEL
Uncertain
0.57
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0030
D
Polyphen
1.0
D
Vest4
0.99
MutPred
0.79
Loss of catalytic residue at A480 (P = 0.0049);
MVP
0.59
MPC
0.59
ClinPred
0.99
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.69
gMVP
0.70

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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.

Other links and lift over

dbSNP: rs1567151506; hg19: chr15-51012187; API