rs6617

Positions:

• chr3-52706166-C-G
• chr3-52706166-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000233025.11(SPCS1):​c.121C>G​(p.Pro41Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.419 in 1,544,598 control chromosomes in the GnomAD database, including 137,888 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.46 (16111 hom., cov: 31)
  • Exomes 𝑓: 0.41 (121777 hom.)
• Consequence: SPCS1 ENST00000233025.11 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.37

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.2408574E-5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPCS1	NM_014041.5	c.-81C>G		5_prime_UTR_variant	1/4	ENST00000619898.5	NP_054760.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPCS1	ENST00000619898.5	c.-81C>G		5_prime_UTR_variant	1/4	1	NM_014041.5	ENSP00000478310	P1

Frequencies

GnomAD3 genomes AF: 0.455 AC: 69102 AN: 151794 Hom.: 16091 Cov.: 31

Gnomad AFR AF: 0.522

Gnomad AMI AF: 0.457

Gnomad AMR AF: 0.523

Gnomad ASJ AF: 0.466

Gnomad EAS AF: 0.428

Gnomad SAS AF: 0.267

Gnomad FIN AF: 0.398

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.423

Gnomad OTH AF: 0.455

GnomAD3 exomes AF: 0.419 AC: 63083 AN: 150414 Hom.: 13926 AF XY: 0.403 AC XY: 32919 AN XY: 81632

Gnomad AFR exome AF: 0.516

Gnomad AMR exome AF: 0.553

Gnomad ASJ exome AF: 0.469

Gnomad EAS exome AF: 0.415

Gnomad SAS exome AF: 0.268

Gnomad FIN exome AF: 0.391

Gnomad NFE exome AF: 0.409

Gnomad OTH exome AF: 0.415

GnomAD4 exome AF: 0.415 AC: 577608 AN: 1392686 Hom.: 121777 Cov.: 58 AF XY: 0.409 AC XY: 281686 AN XY: 688004

Gnomad4 AFR exome AF: 0.532

Gnomad4 AMR exome AF: 0.543

Gnomad4 ASJ exome AF: 0.478

Gnomad4 EAS exome AF: 0.479

Gnomad4 SAS exome AF: 0.270

Gnomad4 FIN exome AF: 0.403

Gnomad4 NFE exome AF: 0.415

Gnomad4 OTH exome AF: 0.410

GnomAD4 genome AF: 0.455 AC: 69177 AN: 151912 Hom.: 16111 Cov.: 31 AF XY: 0.454 AC XY: 33722 AN XY: 74272

Gnomad4 AFR AF: 0.522

Gnomad4 AMR AF: 0.522

Gnomad4 ASJ AF: 0.466

Gnomad4 EAS AF: 0.428

Gnomad4 SAS AF: 0.268

Gnomad4 FIN AF: 0.398

Gnomad4 NFE AF: 0.423

Gnomad4 OTH AF: 0.460

Alfa AF: 0.411 Hom.: 7982

Bravo AF: 0.470

TwinsUK AF: 0.399 AC: 1480

ALSPAC AF: 0.407 AC: 1569

ExAC AF: 0.292 AC: 30753

Asia WGS AF: 0.379 AC: 1317 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.38
DANN	Benign	0.42
DEOGEN2	Benign	0.081	T;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0057	N
LIST_S2	Benign	0.19	.;T
MetaRNN	Benign	0.000042	T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.25	.;N
REVEL	Benign	0.0070
Sift	Benign	1.0	.;T
Sift4G	Benign	1.0	T;T
Vest4		0.028
MPC		0.82
ClinPred		0.0034	T
GERP RS		-4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.075

Splicing

Name	Calibrated prediction	Score	Prediction
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

LitVar

Other links and lift over

dbSNP: rs6617; hg19: chr3-52740182; COSMIC: COSV51776812; COSMIC: COSV51776812;