Genetic Variant SPPL2A:p.Arg483Ser (chr15-50719981-G-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_032802.4(SPPL2A):c.1447C>A(p.Arg483Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,190 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R483H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SPPL2A
NM_032802.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.38

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

immunodeficiency 86
Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia

SPPL2A links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.952

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPPL2A	NM_032802.4	MANE Select	c.1447C>A	p.Arg483Ser	missense	Exon 14 of 15	NP_116191.2
SPPL2A	NM_001438111.1		c.1501C>A	p.Arg501Ser	missense	Exon 15 of 16	NP_001425040.1
SPPL2A	NM_001438112.1		c.1327+2143C>A		intron	N/A	NP_001425041.1	A0A8V8TLZ2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPPL2A	ENST00000261854.10	TSL:1 MANE Select	c.1447C>A	p.Arg483Ser	missense	Exon 14 of 15	ENSP00000261854.5	Q8TCT8
SPPL2A	ENST00000951698.1		c.1504C>A	p.Arg502Ser	missense	Exon 15 of 16	ENSP00000621757.1
SPPL2A	ENST00000951700.1		c.1408C>A	p.Arg470Ser	missense	Exon 15 of 16	ENSP00000621759.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461190

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726944

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33438

American (AMR)

AF:

0.00

AC:

AN:

44568

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39668

South Asian (SAS)

AF:

0.00

AC:

AN:

86188

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111668

Other (OTH)

AF:

0.00

AC:

AN:

60376

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.044

MetaRNN

Pathogenic

0.95

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.8

PhyloP100

4.4

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-5.2

REVEL

Uncertain

0.43

Sift

Uncertain

0.0030

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.91

MutPred

0.84

Loss of methylation at K484 (P = 0.043)

MVP

0.51

MPC

0.62

ClinPred

1.0

GERP RS

5.7

Varity_R

0.87

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over