Genetic Variant NM_021928.4:c.296C>G (chr4-176327163-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_021928.4(SPCS3):c.296C>G(p.Ala99Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000713 in 1,403,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A99V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

SPCS3
NM_021928.4 missense, splice_region

Scores

Splicing: ADA: 0.9528

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.80

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17824787).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021928.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPCS3	NM_021928.4	MANE Select	c.296C>G	p.Ala99Gly	missense splice_region	Exon 4 of 5	NP_068747.1	P61009

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPCS3	ENST00000503362.2	TSL:1 MANE Select	c.296C>G	p.Ala99Gly	missense splice_region	Exon 4 of 5	ENSP00000427463.1	P61009
SPCS3	ENST00000507001.1	TSL:2	n.208C>G		non_coding_transcript_exon	Exon 1 of 2
SPCS3	ENST00000507678.5	TSL:2	n.2332C>G		splice_region non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.13e-7

AC:

AN:

1403006

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

696012

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31056

American (AMR)

AF:

0.00

AC:

AN:

34928

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24842

East Asian (EAS)

AF:

0.00

AC:

AN:

38350

South Asian (SAS)

AF:

0.00

AC:

AN:

76964

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51750

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5662

European-Non Finnish (NFE)

AF:

9.25e-7

AC:

AN:

1081264

Other (OTH)

AF:

0.00

AC:

AN:

58190

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.063

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.041

Eigen

Benign

0.054

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.0024

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.4

PhyloP100

5.8

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.4

REVEL

Benign

0.061

Sift

Benign

0.34

Sift4G

Benign

0.34

Polyphen

0.0010

Vest4

0.35

MutPred

0.26

Gain of disorder (P = 0.1023)

MVP

0.082

MPC

1.2

ClinPred

0.64

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.17

gMVP

0.36

Mutation Taster

=67/33

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.95

dbscSNV1_RF

Benign

0.66

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over