chr12-120768416-G-C

Variant names:

• chr12-120768416-G-C
• NM_139015.5:c.682C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_139015.5(SPPL3):​c.682C>G​(p.Leu228Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SPPL3 NM_139015.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.16

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11116871).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPPL3	NM_139015.5	c.682C>G	p.Leu228Val	missense_variant	Exon 8 of 11	ENST00000353487.7	NP_620584.2
SPPL3	XM_011537925.3	c.682C>G	p.Leu228Val	missense_variant	Exon 8 of 11		XP_011536227.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPPL3	ENST00000353487.7	c.682C>G	p.Leu228Val	missense_variant	Exon 8 of 11	1	NM_139015.5	ENSP00000288680.4
SPPL3	ENST00000545209.1	n.216C>G		non_coding_transcript_exon_variant	Exon 1 of 4	1
SPPL3	ENST00000392495.7	n.1258C>G		non_coding_transcript_exon_variant	Exon 2 of 5	2
SPPL3	ENST00000536996.5	c.*22C>G		downstream_gene_variant		5		ENSP00000442484.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.682C>G (p.L228V) alteration is located in exon 8 (coding exon 8) of the SPPL3 gene. This alteration results from a C to G substitution at nucleotide position 682, causing the leucine (L) at amino acid position 228 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	0.092
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Benign	0.18
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.96	T
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.086
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.32
MVP		0.068
MPC		1.1
ClinPred		0.45	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.091
gMVP		0.25

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-121206219;