dbSNP rs1036965750: SPPL3:p.Arg337Gln (chr12-120766336-C-T) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_139015.5(SPPL3):c.1010G>A(p.Arg337Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000938 in 1,598,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

SPPL3
NM_139015.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.57

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: Likely_benign. The variant received -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.40991074).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPPL3	NM_139015.5 link	c.1010G>A	p.Arg337Gln	missense_variant	Exon 10 of 11	ENST00000353487.7	NP_620584.2	Q8TCT6-2Q9UG23
SPPL3	XM_011537925.3 link	c.1010G>A	p.Arg337Gln	missense_variant	Exon 10 of 11		XP_011536227.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SPPL3	ENST00000353487.7 link	c.1010G>A	p.Arg337Gln	missense_variant	Exon 10 of 11	1	NM_139015.5	ENSP00000288680.4	Q8TCT6-2
SPPL3	ENST00000545209.1 link	n.544G>A		non_coding_transcript_exon_variant	Exon 3 of 4	1
SPPL3	ENST00000392495.7 link	n.1586G>A		non_coding_transcript_exon_variant	Exon 4 of 5	2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000450

AC:

AN:

221982

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000106

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:

0.00000829

AC:

AN:

1446816

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

718046

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33394

American (AMR)

AF:

0.00

AC:

AN:

42086

Ashkenazi Jewish (ASJ)

AF:

0.0000388

AC:

AN:

25770

East Asian (EAS)

AF:

0.00

AC:

AN:

39172

South Asian (SAS)

AF:

0.0000120

AC:

AN:

83246

European-Finnish (FIN)

AF:

0.0000192

AC:

AN:

52066

Middle Eastern (MID)

AF:

0.000696

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.00000271

AC:

AN:

1105464

Other (OTH)

AF:

0.0000167

AC:

AN:

59874

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152094

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41392

American (AMR)

AF:

0.000131

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000902

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 22, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1010G>A (p.R337Q) alteration is located in exon 10 (coding exon 10) of the SPPL3 gene. This alteration results from a G to A substitution at nucleotide position 1010, causing the arginine (R) at amino acid position 337 to be replaced by a glutamine (Q). 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

0.089

BayesDel_addAF

Benign

-0.014

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

(source)

DANN

Uncertain

1.0

Eigen

Benign

0.043

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.022

MetaRNN

Benign

0.41

MetaSVM

Benign

-1.0

PhyloP100

7.6

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.46

REVEL

Benign

0.17

Sift

Benign

0.43

Sift4G

Benign

0.41

Vest4

0.72

MVP

0.19

MPC

1.3

ClinPred

0.63

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.13

gMVP

0.67

Mutation Taster

=32/68

disease causing

(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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rs1036965750

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