rs761247501

Variant names:

• chr3-52706165-A-C
• rs761247501
• ENST00000233025.11:c.120A>C

Your query was ambiguous. Multiple possible variants found:

• chr3-52706165-A-C
• chr3-52706165-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000233025.11(SPCS1):​c.120A>C​(p.Leu40Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000324 in 1,544,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SPCS1 ENST00000233025.11 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0520
• Publications: 0 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: 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=0.07707772).

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.-82A>C		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.120A>C	p.Leu40Phe	missense	Exon 1 of 4	ENSP00000233025.7	Q9Y6A9
	SPCS1	ENST00000619898.5	TSL:1 MANE Select	c.-82A>C		5_prime_UTR	Exon 1 of 4	ENSP00000478310.2	A0A5F9YFS9
	SPCS1	ENST00000918254.1		c.-82A>C		5_prime_UTR	Exon 1 of 4	ENSP00000588313.1

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151408 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000961

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1393372 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 688356

African (AFR) AF: 0.0000629 AC: 2 AN: 31774

American (AMR) AF: 0.00 AC: 0 AN: 36100

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25220

East Asian (EAS) AF: 0.00 AC: 0 AN: 36126

South Asian (SAS) AF: 0.00 AC: 0 AN: 79944

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39122

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5372

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1081620

Other (OTH) AF: 0.00 AC: 0 AN: 58094

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151408 Hom.: 0 Cov.: 33 AF XY: 0.0000270 AC XY: 2 AN XY: 73940

African (AFR) AF: 0.0000243 AC: 1 AN: 41156

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67784

Other (OTH) AF: 0.000961 AC: 2 AN: 2082

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000175 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	7.1
DANN	Benign	0.81
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.077	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.052
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.041
Sift	Benign	0.092	T
Sift4G	Benign	0.071	T
Vest4		0.027
MVP		0.19
MPC		1.0
ClinPred		0.15	T
GERP RS		1.3
PromoterAI		0.098	Neutral
gMVP		0.10
Mutation Taster		=99/1	polymorphism

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: rs761247501; hg19: chr3-52740181;