15-50719969-T-G

Variant names:

• chr15-50719969-T-G
• rs772099878
• NM_032802.4:c.1459A>C

Variant summary

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

The NM_032802.4(SPPL2A):​c.1459A>C​(p.Lys487Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000753 in 1,461,234 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: SPPL2A NM_032802.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.17
• Publications: 0 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 0 ACMG points.

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.1459A>C	p.Lys487Gln	missense	Exon 14 of 15	NP_116191.2
	SPPL2A	NM_001438111.1		c.1513A>C	p.Lys505Gln	missense	Exon 15 of 16	NP_001425040.1
	SPPL2A	NM_001438112.1		c.1327+2155A>C		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.1459A>C	p.Lys487Gln	missense	Exon 14 of 15	ENSP00000261854.5	Q8TCT8
	SPPL2A	ENST00000951698.1		c.1516A>C	p.Lys506Gln	missense	Exon 15 of 16	ENSP00000621757.1
	SPPL2A	ENST00000951700.1		c.1420A>C	p.Lys474Gln	missense	Exon 15 of 16	ENSP00000621759.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000479 AC: 12 AN: 250696 AF XY: 0.0000443

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000350

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461234 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 726976

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.000247 AC: 11 AN: 44546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111810

Other (OTH) AF: 0.00 AC: 0 AN: 60354

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.038	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.2
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.18
Sift	Benign	0.28	T
Sift4G	Benign	0.28	T
Polyphen		1.0	D
Vest4		0.57
MutPred		0.53		Loss of MoRF binding (P = 0.0734)
MVP		0.38
MPC		0.25
ClinPred		0.36	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.48
Mutation Taster		=86/14	polymorphism

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: rs772099878; hg19: chr15-51012166;