15-50720004-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_032802.4(SPPL2A):c.1424C>G(p.Thr475Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0111 in 1,613,522 control chromosomes in the GnomAD database, including 118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0098 (9 hom., cov: 32)
  • Exomes 𝑓: 0.011 (109 hom.)
• Consequence: SPPL2A NM_032802.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.08

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0071602166).
• BP6: Variant 15-50720004-G-C is Benign according to our data. Variant chr15-50720004-G-C is described in ClinVar as [Benign]. Clinvar id is 1166064.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00982 (1496/152310) while in subpopulation EAS AF= 0.0206 (107/5182). AF 95% confidence interval is 0.0175. There are 9 homozygotes in gnomad4. There are 719 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPPL2A	NM_032802.4	c.1424C>G	p.Thr475Ser	missense_variant	14/15	ENST00000261854.10
SPPL2A	XM_005254722.4	c.1478C>G	p.Thr493Ser	missense_variant	15/16
SPPL2A	XM_017022680.2	c.1381+2120C>G		intron_variant
SPPL2A	XM_017022681.2	c.1327+2120C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPPL2A	ENST00000261854.10	c.1424C>G	p.Thr475Ser	missense_variant	14/15	1	NM_032802.4	P1

Frequencies

GnomAD3 genomes AF: 0.00982 AC: 1495 AN: 152192 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00492

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0131

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.0210

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.00943

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0113

Gnomad OTH AF: 0.0143

GnomAD3 exomes AF: 0.0126 AC: 3153 AN: 251208 Hom.: 26 AF XY: 0.0124 AC XY: 1690 AN XY: 135776

Gnomad AFR exome AF: 0.00615

Gnomad AMR exome AF: 0.0189

Gnomad ASJ exome AF: 0.00715

Gnomad EAS exome AF: 0.0178

Gnomad SAS exome AF: 0.0116

Gnomad FIN exome AF: 0.0122

Gnomad NFE exome AF: 0.0114

Gnomad OTH exome AF: 0.0142

GnomAD4 exome AF: 0.0113 AC: 16443 AN: 1461212 Hom.: 109 Cov.: 30 AF XY: 0.0113 AC XY: 8191 AN XY: 726944

Gnomad4 AFR exome AF: 0.00460

Gnomad4 AMR exome AF: 0.0188

Gnomad4 ASJ exome AF: 0.00708

Gnomad4 EAS exome AF: 0.0185

Gnomad4 SAS exome AF: 0.0119

Gnomad4 FIN exome AF: 0.0137

Gnomad4 NFE exome AF: 0.0109

Gnomad4 OTH exome AF: 0.0106

GnomAD4 genome AF: 0.00982 AC: 1496 AN: 152310 Hom.: 9 Cov.: 32 AF XY: 0.00965 AC XY: 719 AN XY: 74476

Gnomad4 AFR AF: 0.00493

Gnomad4 AMR AF: 0.0131

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.0206

Gnomad4 SAS AF: 0.00891

Gnomad4 FIN AF: 0.00943

Gnomad4 NFE AF: 0.0113

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0107 Hom.: 8

Bravo AF: 0.00975

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00986 AC: 38

ESP6500AA AF: 0.00478 AC: 21

ESP6500EA AF: 0.0107 AC: 92

ExAC AF: 0.0128 AC: 1557

Asia WGS AF: 0.0160 AC: 56 AN: 3478

EpiCase AF: 0.0104

EpiControl AF: 0.0119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.063	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.19
Sift	Benign	0.11	T
Sift4G	Benign	0.18	T
Polyphen		0.79	P
Vest4		0.15
MutPred		0.70		Gain of MoRF binding (P = 0.119);
MPC		0.16
ClinPred		0.024	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.30

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

Publications

LitVar

Other links and lift over

dbSNP: rs145209254; hg19: chr15-51012201;