rs387906829

Positions:

• chr9-34637268-C-G
• chr9-34637268-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1_Moderate PM2 PP3_Strong PP5_Very_Strong

The NM_005866.4(SIGMAR1):​c.304G>C​(p.Glu102Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,419,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SIGMAR1 NM_005866.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.69

Genes affected

SIGMAR1 (HGNC:8157): (sigma non-opioid intracellular receptor 1) This gene encodes a receptor protein that interacts with a variety of psychotomimetic drugs, including cocaine and amphetamines. The receptor is believed to play an important role in the cellular functions of various tissues associated with the endocrine, immune, and nervous systems. As indicated by its previous name, opioid receptor sigma 1 (OPRS1), the product of this gene was erroneously thought to function as an opioid receptor; it is now thought to be a non-opioid receptor. Mutations in this gene has been associated with juvenile amyotrophic lateral sclerosis 16. Alternative splicing of this gene results in transcript variants encoding distinct isoforms. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PS1: Transcript NM_005866.4 (SIGMAR1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 9-34637268-C-G is Pathogenic according to our data. Variant chr9-34637268-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 30238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-34637268-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIGMAR1	NM_005866.4	c.304G>C	p.Glu102Gln	missense_variant	2/4	ENST00000277010.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIGMAR1	ENST00000277010.9	c.304G>C	p.Glu102Gln	missense_variant	2/4	1	NM_005866.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1419908 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 703908

Gnomad4 AFR exome AF: 0.00

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: 0.00000183

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2020

The p.E102Q variant (also known as c.304G>C), located in coding exon 2 of the SIGMAR1 gene, results from a G to C substitution at nucleotide position 304. The glutamic acid at codon 102 is replaced by glutamine, an amino acid with highly similar properties. In a large consanguineous family with Middle Eastern ancestry, this variant was reported in the homozygous state and found to segregate with disease in multiple relatives with juvenile amyotrophic lateral sclerosis (Al-Saif A et al. Ann Neurol, 2011 Dec;70:913-9). This variant impacts a region critical to protein function, and several functional studies demonstrate abnormal protein function including mislocalization, aggregation, impaired signaling and reduced cell survival (Al-Saif A et al. Ann Neurol, 2011 Dec;70:913-9; Fukunaga K et al. J Pharmacol Sci, 2015 Jan;127:36-41; Schmidt HR et al. Nature, 2016 Apr;532:527-30; Watanabe S et al. EMBO Mol Med, 2016 12;8:1421-1437; Dreser A et al. Cell Death Differ, 2017 10;24:1655-1671; Abramyan AM et al. Comput Struct Biotechnol J, 2020 Jan;18:199-206; Couly S et al. Hum Mol Genet, 2020 03;29:529-540; Rodríguez-Muñoz M et al. Int J Mol Sci, 2020 Oct;21:7339). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Autosomal recessive distal spinal muscular atrophy 2;C3280587:Amyotrophic lateral sclerosis type 16 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 06, 2022

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SIGMAR1 function (PMID: 21842496, 25175561, 25704016, 27821430, 28622300, 31696229). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 30238). This missense change has been observed in individual(s) with juvenile amyotrophic lateral sclerosis (PMID: 21842496). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 102 of the SIGMAR1 protein (p.Glu102Gln). -

Amyotrophic lateral sclerosis type 16 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	32
DANN	Uncertain	1.0
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.63	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.99
MutPred		0.93		.;Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP		0.83
MPC		1.9
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.98
gMVP		0.99

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: rs387906829; hg19: chr9-34637265;