3-52706166-C-G

Variant names:

• chr3-52706166-C-G
• rs6617
• ENST00000233025.11:c.121C>G

Variant summary

Our verdict is Benign. The variant received -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. 14/18 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
• Publications: 50 publications found

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]

GLT8D1 (HGNC:24870): (glycosyltransferase 8 domain containing 1) This gene encodes a member of the glycosyltransferase family. The specific function of this protein has not been determined. Alternative splicing results in multiple transcript variants of this gene [provided by RefSeq, May 2013]

GLT8D1 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000233025.11. 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
	SPCS1	NM_014041.5	MANE Select	c.-81C>G		5_prime_UTR	Exon 1 of 4	NP_054760.4	A0A5F9YFS9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPCS1	ENST00000233025.11	TSL:1	c.121C>G	p.Pro41Ala	missense	Exon 1 of 4	ENSP00000233025.7	Q9Y6A9
	SPCS1	ENST00000619898.5	TSL:1 MANE Select	c.-81C>G		5_prime_UTR	Exon 1 of 4	ENSP00000478310.2	A0A5F9YFS9
	SPCS1	ENST00000918254.1		c.-81C>G		5_prime_UTR	Exon 1 of 4	ENSP00000588313.1

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

GnomAD2 exomes AF: 0.419 AC: 63083 AN: 150414 AF XY: 0.403

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 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

African (AFR) AF: 0.532 AC: 16901 AN: 31756

American (AMR) AF: 0.543 AC: 19610 AN: 36110

Ashkenazi Jewish (ASJ) AF: 0.478 AC: 12051 AN: 25214

East Asian (EAS) AF: 0.479 AC: 17304 AN: 36126

South Asian (SAS) AF: 0.270 AC: 21592 AN: 79958

European-Finnish (FIN) AF: 0.403 AC: 15561 AN: 38584

Middle Eastern (MID) AF: 0.433 AC: 2314 AN: 5338

European-Non Finnish (NFE) AF: 0.415 AC: 448493 AN: 1081546

Other (OTH) AF: 0.410 AC: 23782 AN: 58054

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

African (AFR) AF: 0.522 AC: 21640 AN: 41426

American (AMR) AF: 0.522 AC: 7979 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.466 AC: 1616 AN: 3470

East Asian (EAS) AF: 0.428 AC: 2198 AN: 5138

South Asian (SAS) AF: 0.268 AC: 1291 AN: 4816

European-Finnish (FIN) AF: 0.398 AC: 4215 AN: 10580

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.423 AC: 28711 AN: 67896

Other (OTH) AF: 0.460 AC: 968 AN: 2106

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 v4.9

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
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
MetaSVM	Benign	-0.95	T
PhyloP100		-1.4
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.25	N
REVEL	Benign	0.0070
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.028
MPC		0.82
ClinPred		0.0034	T
GERP RS		-4.4
PromoterAI		0.081	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.075
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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