chr15-50756405-G-C

Variant names:

• chr15-50756405-G-C
• rs12915708
• NM_032802.4:c.67-6659C>G

Variant summary

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

The NM_032802.4(SPPL2A):​c.67-6659C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 146,776 control chromosomes in the GnomAD database, including 5,560 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 0.25 (5560 hom., cov: 28)
• Consequence: SPPL2A NM_032802.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.511
• Publications: 12 publications found

Genes affected

SPPL2A (HGNC:30227): (signal peptide peptidase like 2A) This gene encodes a member of the GXGD family of aspartic proteases, which are transmembrane proteins with two conserved catalytic motifs localized within the membrane-spanning regions, as well as a member of the signal peptide peptidase-like protease (SPPL) family. This protein is expressed in all major adult human tissues and localizes to late endosomal compartments and lysosomal membranes. A pseudogene of this gene also lies on chromosome 15. [provided by RefSeq, Feb 2012]

SPPL2A Gene-Disease associations (from GenCC):

• immunodeficiency 86

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.532 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPPL2A	NM_032802.4	c.67-6659C>G		intron_variant	Intron 1 of 14	ENST00000261854.10	NP_116191.2
SPPL2A	NM_001438111.1	c.67-6659C>G		intron_variant	Intron 1 of 15		NP_001425040.1
SPPL2A	NM_001438112.1	c.67-6659C>G		intron_variant	Intron 1 of 13		NP_001425041.1
SPPL2A	XM_017022680.2	c.67-6659C>G		intron_variant	Intron 1 of 14		XP_016878169.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPPL2A	ENST00000261854.10	c.67-6659C>G		intron_variant	Intron 1 of 14	1	NM_032802.4	ENSP00000261854.5

Frequencies

GnomAD3 genomes AF: 0.253 AC: 37096 AN: 146708 Hom.: 5555 Cov.: 28

Gnomad AFR AF: 0.0941

Gnomad AMI AF: 0.408

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.549

Gnomad SAS AF: 0.278

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.316

Gnomad OTH AF: 0.278

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

GnomAD4 genome AF: 0.253 AC: 37115 AN: 146776 Hom.: 5560 Cov.: 28 AF XY: 0.256 AC XY: 18212 AN XY: 71256

African (AFR) AF: 0.0941 AC: 3734 AN: 39694

American (AMR) AF: 0.237 AC: 3425 AN: 14470

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 748 AN: 3428

East Asian (EAS) AF: 0.549 AC: 2738 AN: 4984

South Asian (SAS) AF: 0.279 AC: 1291 AN: 4632

European-Finnish (FIN) AF: 0.323 AC: 3006 AN: 9316

Middle Eastern (MID) AF: 0.266 AC: 73 AN: 274

European-Non Finnish (NFE) AF: 0.316 AC: 21164 AN: 67046

Other (OTH) AF: 0.280 AC: 570 AN: 2036

Alfa AF: 0.272 Hom.: 786

Bravo AF: 0.237

Asia WGS AF: 0.386 AC: 1340 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.7
DANN	Benign	0.71
PhyloP100		-0.51
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: rs12915708; hg19: chr15-51048602;