rs796065352

Variant names:

• chr9-34637546-C-A
• rs796065352
• ENST00000461426.1:n.251G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The ENST00000461426.1(SIGMAR1):​n.251G>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000189 in 1,585,160 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SIGMAR1 ENST00000461426.1 non_coding_transcript_exon
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.45
• Publications: 9 publications found

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]

SIGMAR1 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis type 16

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• autosomal recessive distal spinal muscular atrophy 2

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• juvenile amyotrophic lateral sclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 9-34637546-C-A is Pathogenic according to our data. Variant chr9-34637546-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 208123.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000461426.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIGMAR1	NM_005866.4	MANE Select	c.151+1G>T		splice_donor intron	N/A	NP_005857.1
	SIGMAR1	NM_001282207.2		c.91+61G>T		intron	N/A	NP_001269136.1
	SIGMAR1	NM_147157.3		c.151+1G>T		splice_donor intron	N/A	NP_671513.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIGMAR1	ENST00000461426.1	TSL:1	n.251G>T		non_coding_transcript_exon	Exon 1 of 2
	SIGMAR1	ENST00000277010.9	TSL:1 MANE Select	c.151+1G>T		splice_donor intron	N/A	ENSP00000277010.4
	SIGMAR1	ENST00000477726.1	TSL:1	c.151+1G>T		splice_donor intron	N/A	ENSP00000420022.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152258 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1432902 Hom.: 0 Cov.: 32 AF XY: 0.00000141 AC XY: 1 AN XY: 711548

African (AFR) AF: 0.00 AC: 0 AN: 32892

American (AMR) AF: 0.00 AC: 0 AN: 42448

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25708

East Asian (EAS) AF: 0.00 AC: 0 AN: 38330

South Asian (SAS) AF: 0.0000240 AC: 2 AN: 83370

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42814

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102108

Other (OTH) AF: 0.00 AC: 0 AN: 59484

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152258 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74392

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Autosomal recessive distal spinal muscular atrophy 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		1.4
GERP RS		4.6
PromoterAI		-0.34	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=202/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.46		Position offset: 9
DS_DL_spliceai		1.0		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs796065352; hg19: chr9-34637543;