12-120810884-G-C

Variant names:

• chr12-120810884-G-C
• rs143911453
• NM_139015.5:c.26C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_139015.5(SPPL3):​c.26C>G​(p.Ala9Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. A9V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SPPL3 NM_139015.5 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.73
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23605204).

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.26C>G	p.Ala9Gly	missense splice_region	Exon 2 of 11	NP_620584.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPPL3	ENST00000353487.7	TSL:1 MANE Select	c.26C>G	p.Ala9Gly	missense splice_region	Exon 2 of 11	ENSP00000288680.4	Q8TCT6-2
	SPPL3	ENST00000961961.1		c.26C>G	p.Ala9Gly	missense splice_region	Exon 2 of 11	ENSP00000632020.1
	SPPL3	ENST00000913320.1		c.26C>G	p.Ala9Gly	missense splice_region	Exon 2 of 10	ENSP00000583379.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250932 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459750 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726352

African (AFR) AF: 0.00 AC: 0 AN: 33408

American (AMR) AF: 0.0000224 AC: 1 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39620

South Asian (SAS) AF: 0.00 AC: 0 AN: 86172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110310

Other (OTH) AF: 0.00 AC: 0 AN: 60302

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.0055	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.070	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		8.7
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.20
Sift	Benign	0.20	T
Sift4G	Benign	0.44	T
Polyphen		0.36	B
Vest4		0.56
MutPred		0.29		Gain of catalytic residue at Y10 (P = 0.0191)
MVP		0.068
MPC		1.1
ClinPred		0.69	D
GERP RS		5.0
Varity_R		0.27
gMVP		0.27
Mutation Taster		=30/70	disease causing

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

Other links and lift over

dbSNP: rs143911453; hg19: chr12-121248687;