rs752650184

Variant names:

• chr4-176327163-C-A
• NM_021928.4:c.296C>A

Your query was ambiguous. Multiple possible variants found:

• chr4-176327163-C-A
• chr4-176327163-C-G
• chr4-176327163-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021928.4(SPCS3):​c.296C>A​(p.Ala99Asp) 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. 13/22 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SPCS3 NM_021928.4 missense, splice_region
• Scores: Splicing: ADA: 0.7677
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.80

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18373361).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPCS3	NM_021928.4	c.296C>A	p.Ala99Asp	missense_variant, splice_region_variant	Exon 4 of 5	ENST00000503362.2	NP_068747.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPCS3	ENST00000503362.2	c.296C>A	p.Ala99Asp	missense_variant, splice_region_variant	Exon 4 of 5	1	NM_021928.4	ENSP00000427463.1
SPCS3	ENST00000507001.1	n.208C>A		non_coding_transcript_exon_variant	Exon 1 of 2	2
SPCS3	ENST00000507678.5	n.2332C>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 4	2
SPCS3	ENST00000513139.1	n.371C>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.13e-7 AC: 1 AN: 1403006 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 696012

Gnomad4 AFR exome AF: 0.0000322

Gnomad4 AMR exome AF: 0.00

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.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.0037	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.0017
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.6	L
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.10
Sift	Benign	0.55	T
Sift4G	Benign	0.56	T
Polyphen		0.014	B
Vest4		0.49
MutPred		0.29		Gain of disorder (P = 0.0716);
MVP		0.043
MPC		1.7
ClinPred		0.64	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.77
dbscSNV1_RF	Benign	0.39
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-177248314;