rs6489780

Variant names:

• chr12-120790607-C-G
• rs6489780
• NM_139015.5:c.190+862G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_139015.5(SPPL3):​c.190+862G>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 152,104 control chromosomes in the GnomAD database, including 4,507 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 (4507 hom., cov: 32)
• Consequence: SPPL3 NM_139015.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.190
• Publications: 7 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPPL3	NM_139015.5	c.190+862G>C		intron_variant	Intron 3 of 10	ENST00000353487.7	NP_620584.2
SPPL3	XM_011537925.3	c.190+862G>C		intron_variant	Intron 3 of 10		XP_011536227.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPPL3	ENST00000353487.7	c.190+862G>C		intron_variant	Intron 3 of 10	1	NM_139015.5	ENSP00000288680.4

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29487 AN: 151986 Hom.: 4500 Cov.: 32

Gnomad AFR AF: 0.408

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.0599

Gnomad EAS AF: 0.402

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.0839

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.0808

Gnomad OTH AF: 0.161

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

GnomAD4 genome AF: 0.194 AC: 29527 AN: 152104 Hom.: 4507 Cov.: 32 AF XY: 0.194 AC XY: 14447 AN XY: 74368

African (AFR) AF: 0.408 AC: 16900 AN: 41470

American (AMR) AF: 0.154 AC: 2352 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0599 AC: 208 AN: 3470

East Asian (EAS) AF: 0.402 AC: 2077 AN: 5166

South Asian (SAS) AF: 0.232 AC: 1118 AN: 4816

European-Finnish (FIN) AF: 0.0839 AC: 889 AN: 10596

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.0808 AC: 5495 AN: 67982

Other (OTH) AF: 0.159 AC: 336 AN: 2112

Alfa AF: 0.140 Hom.: 340

Bravo AF: 0.212

Asia WGS AF: 0.311 AC: 1082 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.0
DANN	Benign	0.58
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6489780; hg19: chr12-121228410; COSMIC: COSV107438296;