9-34635601-T-C

Variant names:

• chr9-34635601-T-C
• rs4879809
• ENST00000353468.4:n.*335A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The ENST00000353468.4(SIGMAR1):​n.*335A>G 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 0.997 in 1,613,774 control chromosomes in the GnomAD database, including 802,134 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (74404 hom., cov: 36)
  • Exomes 𝑓: 1.0 (727730 hom.)
• Consequence: SIGMAR1 ENST00000353468.4 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:5
• Conservation: PhyloP100: 0.436
• Publications: 20 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 9-34635601-T-C is Benign according to our data. Variant chr9-34635601-T-C is described in ClinVar as Benign. ClinVar VariationId is 208122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIGMAR1	NM_005866.4	c.*31A>G		3_prime_UTR_variant	Exon 4 of 4	ENST00000277010.9	NP_005857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIGMAR1	ENST00000277010.9	c.*31A>G		3_prime_UTR_variant	Exon 4 of 4	1	NM_005866.4	ENSP00000277010.4

Frequencies

GnomAD3 genomes AF: 0.988 AC: 150443 AN: 152250 Hom.: 74351 Cov.: 36

Gnomad AFR AF: 0.961

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.995

Gnomad ASJ AF: 0.998

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.989

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.991

GnomAD2 exomes AF: 0.996 AC: 248455 AN: 249560 AF XY: 0.996

Gnomad AFR exome AF: 0.960

Gnomad AMR exome AF: 0.997

Gnomad ASJ exome AF: 0.998

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.996

GnomAD4 exome AF: 0.998 AC: 1458373 AN: 1461406 Hom.: 727730 Cov.: 60 AF XY: 0.998 AC XY: 725359 AN XY: 726978

African (AFR) AF: 0.959 AC: 32090 AN: 33478

American (AMR) AF: 0.997 AC: 44566 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.998 AC: 26054 AN: 26116

East Asian (EAS) AF: 1.00 AC: 39698 AN: 39698

South Asian (SAS) AF: 0.991 AC: 85364 AN: 86162

European-Finnish (FIN) AF: 1.00 AC: 53336 AN: 53336

Middle Eastern (MID) AF: 0.994 AC: 5719 AN: 5752

European-Non Finnish (NFE) AF: 1.00 AC: 1111443 AN: 1111806

Other (OTH) AF: 0.996 AC: 60103 AN: 60364

GnomAD4 genome AF: 0.988 AC: 150555 AN: 152368 Hom.: 74404 Cov.: 36 AF XY: 0.988 AC XY: 73622 AN XY: 74498

African (AFR) AF: 0.961 AC: 39956 AN: 41584

American (AMR) AF: 0.995 AC: 15227 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.998 AC: 3464 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5178 AN: 5178

South Asian (SAS) AF: 0.989 AC: 4779 AN: 4830

European-Finnish (FIN) AF: 1.00 AC: 10628 AN: 10628

Middle Eastern (MID) AF: 0.993 AC: 292 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68022 AN: 68044

Other (OTH) AF: 0.991 AC: 2097 AN: 2116

Alfa AF: 0.997 Hom.: 13642

Bravo AF: 0.986

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyotrophic lateral sclerosis type 16 Uncertain:1 Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 24, 2015

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26205306) -

Autosomal recessive distal spinal muscular atrophy 2 Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Benign	0.81
PhyloP100		0.44
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs4879809; hg19: chr9-34635598;