Genetic Variant SPPL3:p.Ile78Val (chr12-120784552-T-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_139015.5(SPPL3):c.232A>G(p.Ile78Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000531 in 1,612,894 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00055 ( 2 hom. )

Consequence

SPPL3
NM_139015.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.45

Publications

0 publications found

Variant links:

Genes affected

SPPL3 (HGNC:30424): (signal peptide peptidase like 3) Enables aspartic endopeptidase activity, intramembrane cleaving and protein homodimerization activity. Involved in several processes, including T cell receptor signaling pathway; positive regulation of calcineurin-NFAT signaling cascade; and positive regulation of protein dephosphorylation. Located in Golgi-associated vesicle membrane; plasma membrane; and rough endoplasmic reticulum. Is integral component of cytoplasmic side of endoplasmic reticulum membrane and integral component of lumenal side of endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

SPPL3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.057269454).

BS2

High Homozygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPPL3	NM_139015.5 link	c.232A>G	p.Ile78Val	missense_variant	Exon 4 of 11	ENST00000353487.7	NP_620584.2	Q8TCT6-2Q9UG23
SPPL3	XM_011537925.3 link	c.232A>G	p.Ile78Val	missense_variant	Exon 4 of 11		XP_011536227.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPPL3	ENST00000353487.7 link	c.232A>G	p.Ile78Val	missense_variant	Exon 4 of 11	1	NM_139015.5	ENSP00000288680.4		Q8TCT6-2

Frequencies

GnomAD3 genomes

AF:

0.000381

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000647

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000260

AC:

AN:

250076

AF XY:

0.000281

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000321

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000397

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.000547

AC:

799

AN:

1460748

Hom.:

Cov.:

AF XY:

0.000531

AC XY:

386

AN XY:

726708

show subpopulations

African (AFR)

AF:

0.0000898

AC:

AN:

33424

American (AMR)

AF:

0.000404

AC:

AN:

44604

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39656

South Asian (SAS)

AF:

0.000116

AC:

AN:

86044

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000664

AC:

738

AN:

1111426

Other (OTH)

AF:

0.000431

AC:

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

108

144

180

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000381

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.000350

AC XY:

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41436

American (AMR)

AF:

0.000327

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000647

AC:

AN:

68006

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.526

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000523

Hom.:

Bravo

AF:

0.000431

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000255

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000416

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 10, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.232A>G (p.I78V) alteration is located in exon 4 (coding exon 4) of the SPPL3 gene. This alteration results from a A to G substitution at nucleotide position 232, causing the isoleucine (I) at amino acid position 78 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.65

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.47

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

D;D;D;D;D

M_CAP

Benign

0.039

MetaRNN

Benign

0.057

T;T;T;T;T

MetaSVM

Benign

-1.0

PhyloP100

7.5

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.48

N;N;N;N;N

REVEL

Benign

0.22

Sift

Benign

0.52

T;T;T;T;D

Sift4G

Benign

0.49

T;T;.;.;.

Vest4

0.43

MVP

0.043

MPC

0.92

ClinPred

0.053

GERP RS

4.7

Varity_R

0.048

gMVP

0.41

Mutation Taster

=77/23

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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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12-120784552-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over