dbSNP rs662739: SPPL3:c.102-533A>G (chr12-120792090-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_139015.5(SPPL3):c.102-533A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.755 in 153,004 control chromosomes in the GnomAD database, including 44,655 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.76 ( 44471 hom., cov: 31)

Exomes 𝑓: 0.61 ( 184 hom. )

Consequence

SPPL3
NM_139015.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.868

Publications

13 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.903 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139015.5. 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
	SPPL3	NM_139015.5	MANE Select	c.102-533A>G		intron	N/A	NP_620584.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SPPL3	ENST00000353487.7	TSL:1 MANE Select	c.102-533A>G	intron	N/A	ENSP00000288680.4	Q8TCT6-2
SPPL3	ENST00000961961.1		c.102-533A>G	intron	N/A	ENSP00000632020.1
SPPL3	ENST00000855477.1		c.24-533A>G	intron	N/A	ENSP00000525536.1

Frequencies

GnomAD3 genomes

AF:

0.755

AC:

114778

AN:

151984

Hom.:

44416

Cov.:

show subpopulations

Gnomad AFR

AF:

0.911

Gnomad AMI

AF:

0.805

Gnomad AMR

AF:

0.803

Gnomad ASJ

AF:

0.749

Gnomad EAS

AF:

0.846

Gnomad SAS

AF:

0.890

Gnomad FIN

AF:

0.649

Gnomad MID

AF:

0.810

Gnomad NFE

AF:

0.649

Gnomad OTH

AF:

0.734

GnomAD4 exome

AF:

0.614

AC:

554

AN:

902

Hom.:

184

AF XY:

0.617

AC XY:

333

AN XY:

540

show subpopulations

African (AFR)

AF:

1.00

AC:

AN:

American (AMR)

AF:

0.735

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.875

AC:

AN:

East Asian (EAS)

AF:

0.778

AC:

AN:

South Asian (SAS)

AF:

0.813

AC:

AN:

European-Finnish (FIN)

AF:

0.773

AC:

AN:

Middle Eastern (MID)

AF:

1.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.588

AC:

433

AN:

736

Other (OTH)

AF:

0.583

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

AF:

0.755

AC:

114892

AN:

152102

Hom.:

44471

Cov.:

AF XY:

0.764

AC XY:

56795

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.911

AC:

37846

AN:

41536

American (AMR)

AF:

0.804

AC:

12284

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.749

AC:

2600

AN:

3472

East Asian (EAS)

AF:

0.846

AC:

4371

AN:

5166

South Asian (SAS)

AF:

0.890

AC:

4283

AN:

4814

European-Finnish (FIN)

AF:

0.649

AC:

6862

AN:

10566

Middle Eastern (MID)

AF:

0.810

AC:

238

AN:

294

European-Non Finnish (NFE)

AF:

0.649

AC:

44123

AN:

67946

Other (OTH)

AF:

0.736

AC:

1552

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1354

2709

4063

5418

6772

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

846

1692

2538

3384

4230

<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:

0.691

Hom.:

18630

Bravo

AF:

0.771

Asia WGS

AF:

0.854

AC:

2967

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

0.52

(source)

DANN

Benign

0.42

PhyloP100

-0.87

Mutation Taster

=100/0

polymorphism (auto)

(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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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