Genetic Variant SPCS3:p.Thr177Met (chr4-176328317-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_021928.4(SPCS3):c.530C>T(p.Thr177Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000104 in 1,440,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

SPCS3
NM_021928.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.66

Variant links:

Genes affected

SPCS3 (HGNC:26212): (signal peptidase complex subunit 3) Predicted to enable peptidase activity. Involved in proteolysis and viral protein processing. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

SPCS3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1056107).

BS2

High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPCS3	NM_021928.4 link	c.530C>T	p.Thr177Met	missense_variant	Exon 5 of 5	ENST00000503362.2	NP_068747.1	P61009

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SPCS3	ENST00000503362.2 link	c.530C>T	p.Thr177Met	missense_variant	Exon 5 of 5	1	NM_021928.4	ENSP00000427463.1	P61009
SPCS3	ENST00000507001.1 link	n.442C>T		non_coding_transcript_exon_variant	Exon 2 of 2	2
SPCS3	ENST00000507678.5 link	n.2566C>T		non_coding_transcript_exon_variant	Exon 4 of 4	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000170

AC:

AN:

235228

Hom.:

AF XY:

0.0000156

AC XY:

AN XY:

127818

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000117

Gnomad SAS exome

AF:

0.0000360

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000918

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000104

AC:

AN:

1440318

Hom.:

Cov.:

AF XY:

0.00000839

AC XY:

AN XY:

714914

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000102

Gnomad4 SAS exome

AF:

0.0000609

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000454

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000828

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.530C>T (p.T177M) alteration is located in exon 5 (coding exon 5) of the SPCS3 gene. This alteration results from a C to T substitution at nucleotide position 530, causing the threonine (T) at amino acid position 177 to be replaced by a methionine (M). 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

0.098

BayesDel_addAF

Benign

-0.066

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.029

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.83

M_CAP

Benign

0.0033

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.68

MutationAssessor

Benign

1.8

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.3

REVEL

Benign

0.13

Sift

Benign

0.034

Sift4G

Uncertain

0.060

Polyphen

0.10

Vest4

0.086

MutPred

0.19

Loss of methylation at K178 (P = 0.0311);

MVP

0.12

MPC

1.2

ClinPred

0.22

GERP RS

5.4

Varity_R

0.16

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over