Genetic Variant NM_032802.4:c.1424C>G (chr15-50720004-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_032802.4(SPPL2A):c.1424C>G(p.Thr475Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0111 in 1,613,522 control chromosomes in the GnomAD database, including 118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0098 ( 9 hom., cov: 32)

Exomes 𝑓: 0.011 ( 109 hom. )

Consequence

SPPL2A
NM_032802.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 7.08

Publications

9 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0071602166).

BP6

Variant 15-50720004-G-C is Benign according to our data. Variant chr15-50720004-G-C is described in ClinVar as Benign. ClinVar VariationId is 1166064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00982 (1496/152310) while in subpopulation EAS AF = 0.0206 (107/5182). AF 95% confidence interval is 0.0175. There are 9 homozygotes in GnomAd4. There are 719 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

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.1424C>G	p.Thr475Ser	missense	Exon 14 of 15	NP_116191.2
SPPL2A	NM_001438111.1		c.1478C>G	p.Thr493Ser	missense	Exon 15 of 16	NP_001425040.1
SPPL2A	NM_001438112.1		c.1327+2120C>G		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.1424C>G	p.Thr475Ser	missense	Exon 14 of 15	ENSP00000261854.5	Q8TCT8
SPPL2A	ENST00000951698.1		c.1481C>G	p.Thr494Ser	missense	Exon 15 of 16	ENSP00000621757.1
SPPL2A	ENST00000951700.1		c.1385C>G	p.Thr462Ser	missense	Exon 15 of 16	ENSP00000621759.1

Frequencies

GnomAD3 genomes

AF:

0.00982

AC:

1495

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00492

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.0131

Gnomad ASJ

AF:

0.00922

Gnomad EAS

AF:

0.0210

Gnomad SAS

AF:

0.00849

Gnomad FIN

AF:

0.00943

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0113

Gnomad OTH

AF:

0.0143

GnomAD2 exomes

AF:

0.0126

AC:

3153

AN:

251208

AF XY:

0.0124

show subpopulations

Gnomad AFR exome

AF:

0.00615

Gnomad AMR exome

AF:

0.0189

Gnomad ASJ exome

AF:

0.00715

Gnomad EAS exome

AF:

0.0178

Gnomad FIN exome

AF:

0.0122

Gnomad NFE exome

AF:

0.0114

Gnomad OTH exome

AF:

0.0142

GnomAD4 exome

AF:

0.0113

AC:

16443

AN:

1461212

Hom.:

109

Cov.:

AF XY:

0.0113

AC XY:

8191

AN XY:

726944

show subpopulations

African (AFR)

AF:

0.00460

AC:

154

AN:

33468

American (AMR)

AF:

0.0188

AC:

841

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.00708

AC:

185

AN:

26120

East Asian (EAS)

AF:

0.0185

AC:

734

AN:

39672

South Asian (SAS)

AF:

0.0119

AC:

1025

AN:

86224

European-Finnish (FIN)

AF:

0.0137

AC:

732

AN:

53404

Middle Eastern (MID)

AF:

0.00971

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0109

AC:

12073

AN:

1111518

Other (OTH)

AF:

0.0106

AC:

643

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

736

1472

2208

2944

3680

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

462

924

1386

1848

2310

<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

AF:

0.00982

AC:

1496

AN:

152310

Hom.:

Cov.:

AF XY:

0.00965

AC XY:

719

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00493

AC:

205

AN:

41580

American (AMR)

AF:

0.0131

AC:

200

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00922

AC:

AN:

3470

East Asian (EAS)

AF:

0.0206

AC:

107

AN:

5182

South Asian (SAS)

AF:

0.00891

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00943

AC:

100

AN:

10606

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0113

AC:

771

AN:

68030

Other (OTH)

AF:

0.0142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

160

241

321

401

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0107

Hom.:

Bravo

AF:

0.00975

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.00986

AC:

ESP6500AA

AF:

0.00478

AC:

ESP6500EA

AF:

0.0107

AC:

ExAC

AF:

0.0128

AC:

1557

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.0104

EpiControl

AF:

0.0119

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.50

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.063

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0072

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

PhyloP100

7.1

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.19

Sift

Benign

0.11

Sift4G

Benign

0.18

Polyphen

0.79

Vest4

0.15

MutPred

0.70

Gain of MoRF binding (P = 0.119)

MPC

0.16

ClinPred

0.024

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.39

gMVP

0.30

Mutation Taster

=80/20

polymorphism

(source)

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

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over