3-52707708-A-C

Variant names:

• chr3-52707708-A-C
• rs1379356068
• NM_014041.5:c.205A>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014041.5(SPCS1):​c.205A>C​(p.Ile69Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPCS1 NM_014041.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.44

Genes affected

SPCS1 (HGNC:23401): (signal peptidase complex subunit 1) Predicted to enable peptidase activity and ribosome binding activity. Involved in viral protein processing and virion assembly. Is integral component of endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3257798).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPCS1	NM_014041.5	c.205A>C	p.Ile69Leu	missense_variant	Exon 4 of 4	ENST00000619898.5	NP_054760.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPCS1	ENST00000619898.5	c.205A>C	p.Ile69Leu	missense_variant	Exon 4 of 4	1	NM_014041.5	ENSP00000478310.2
SPCS1	ENST00000233025.11	c.406A>C	p.Ile136Leu	missense_variant	Exon 4 of 4	1		ENSP00000233025.7
SPCS1	ENST00000423431.5	c.139A>C	p.Ile47Leu	missense_variant	Exon 4 of 4	3		ENSP00000391610.1
SPCS1	ENST00000474945.1	n.670A>C		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.406A>C (p.I136L) alteration is located in exon 4 (coding exon 4) of the SPCS1 gene. This alteration results from a A to C substitution at nucleotide position 406, causing the isoleucine (I) at amino acid position 136 to be replaced by a leucine (L). 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	0.16
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	T;T;T;T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;.;D;.
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.33	T;T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	0.99	.;.;.;L
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.28	N;.;N;.
REVEL	Uncertain	0.32
Sift	Benign	0.45	T;.;T;.
Sift4G	Benign	0.55	T;T;T;T
Vest4		0.33
MVP		0.86
MPC		1.2
ClinPred		0.78	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.60
gMVP		0.67

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: rs1379356068; hg19: chr3-52741724;