dbSNP rs373983344: SPCS3:p.His165Gln (chr4-176328282-C-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_021928.4(SPCS3):c.495C>A(p.His165Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 1,458,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

SPCS3
NM_021928.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.102

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.032459915).

BS2

High AC in GnomAdExome4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPCS3	NM_021928.4 link	c.495C>A	p.His165Gln	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.495C>A	p.His165Gln	missense_variant	Exon 5 of 5	1	NM_021928.4	ENSP00000427463.1	P61009
SPCS3	ENST00000507001.1 link	n.407C>A		non_coding_transcript_exon_variant	Exon 2 of 2	2
SPCS3	ENST00000507678.5 link	n.2531C>A		non_coding_transcript_exon_variant	Exon 4 of 4	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000892

AC:

AN:

246690

Hom.:

AF XY:

0.0000598

AC XY:

AN XY:

133880

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000653

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1458228

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

725298

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000590

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.495C>A (p.H165Q) alteration is located in exon 5 (coding exon 5) of the SPCS3 gene. This alteration results from a C to A substitution at nucleotide position 495, causing the histidine (H) at amino acid position 165 to be replaced by a glutamine (Q). 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

0.086

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.51

CADD

Benign

6.1

DANN

Benign

0.76

DEOGEN2

Benign

0.021

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.73

M_CAP

Benign

0.0041

MetaRNN

Benign

0.032

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.37

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.47

REVEL

Benign

0.25

Sift

Benign

0.63

Sift4G

Benign

0.40

Polyphen

0.0010

Vest4

0.16

MutPred

0.34

Gain of sheet (P = 0.1451);

MVP

0.068

MPC

1.2

ClinPred

0.028

GERP RS

-0.029

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.085

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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