chr15-50720004-G-A

Variant names:

• chr15-50720004-G-A
• rs145209254
• NM_032802.4:c.1424C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_032802.4(SPPL2A):​c.1424C>T​(p.Thr475Ile) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T475S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPPL2A NM_032802.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.08
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• immunodeficiency 86

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032802.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPPL2A	NM_032802.4	MANE Select	c.1424C>T	p.Thr475Ile	missense	Exon 14 of 15	NP_116191.2
	SPPL2A	NM_001438111.1		c.1478C>T	p.Thr493Ile	missense	Exon 15 of 16	NP_001425040.1
	SPPL2A	NM_001438112.1		c.1327+2120C>T		intron	N/A	NP_001425041.1	A0A8V8TLZ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPPL2A	ENST00000261854.10	TSL:1 MANE Select	c.1424C>T	p.Thr475Ile	missense	Exon 14 of 15	ENSP00000261854.5	Q8TCT8
	SPPL2A	ENST00000951698.1		c.1481C>T	p.Thr494Ile	missense	Exon 15 of 16	ENSP00000621757.1
	SPPL2A	ENST00000951700.1		c.1385C>T	p.Thr462Ile	missense	Exon 15 of 16	ENSP00000621759.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.068	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.1
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.034	D
Polyphen		0.99	D
Vest4		0.86
MutPred		0.75		Loss of catalytic residue at T475 (P = 0.0941)
MVP		0.46
MPC		0.34
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.64

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

Other links and lift over

dbSNP: rs145209254; hg19: chr15-51012201;