12-120843036-A-G

Position:

• chr12-120843036-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_139015.5(SPPL3):​c.24-32150T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 152,074 control chromosomes in the GnomAD database, including 4,524 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 0.19 (4524 hom., cov: 31)
• Consequence: SPPL3 NM_139015.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.412

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.403 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPPL3	NM_139015.5	c.24-32150T>C		intron_variant		ENST00000353487.7	NP_620584.2
SPPL3	XM_011537925.3	c.23+23483T>C		intron_variant			XP_011536227.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPPL3	ENST00000353487.7	c.24-32150T>C		intron_variant		1	NM_139015.5	ENSP00000288680.4
SPPL3	ENST00000536996.5	c.-88-32150T>C		intron_variant		5		ENSP00000442484.1
SPPL3	ENST00000543608.5	c.-88-32150T>C		intron_variant		3		ENSP00000437603.1
SPPL3	ENST00000543854.5	c.-146-32150T>C		intron_variant		5		ENSP00000439390.1

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29444 AN: 151954 Hom.: 4518 Cov.: 31

Gnomad AFR AF: 0.408

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.0599

Gnomad EAS AF: 0.403

Gnomad SAS AF: 0.231

Gnomad FIN AF: 0.0838

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0803

Gnomad OTH AF: 0.160

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.194 AC: 29481 AN: 152074 Hom.: 4524 Cov.: 31 AF XY: 0.194 AC XY: 14446 AN XY: 74386

Gnomad4 AFR AF: 0.408

Gnomad4 AMR AF: 0.153

Gnomad4 ASJ AF: 0.0599

Gnomad4 EAS AF: 0.403

Gnomad4 SAS AF: 0.231

Gnomad4 FIN AF: 0.0838

Gnomad4 NFE AF: 0.0803

Gnomad4 OTH AF: 0.158

Alfa AF: 0.129 Hom.: 720

Bravo AF: 0.212

Asia WGS AF: 0.312 AC: 1085 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.1
DANN	Benign	0.70

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

LitVar

Other links and lift over

dbSNP: rs10431387; hg19: chr12-121280839;