chr9-34635681-C-A

Variant names:

• chr9-34635681-C-A
• rs541996857
• NM_005866.4:c.623G>T

Variant summary

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

The NM_005866.4(SIGMAR1):​c.623G>T​(p.Arg208Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R208W) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SIGMAR1 NM_005866.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.66
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005866.4. 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
	SIGMAR1	NM_005866.4	MANE Select	c.623G>T	p.Arg208Leu	missense	Exon 4 of 4	NP_005857.1	Q99720-1
	SIGMAR1	NM_001282207.2		c.563G>T	p.Arg188Leu	missense	Exon 4 of 4	NP_001269136.1	Q99720-2
	SIGMAR1	NM_147157.3		c.530G>T	p.Arg177Leu	missense	Exon 3 of 3	NP_671513.1	Q99720-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIGMAR1	ENST00000277010.9	TSL:1 MANE Select	c.623G>T	p.Arg208Leu	missense	Exon 4 of 4	ENSP00000277010.4	Q99720-1
	SIGMAR1	ENST00000477726.1	TSL:1	c.530G>T	p.Arg177Leu	missense	Exon 3 of 3	ENSP00000420022.1	Q99720-3
	SIGMAR1	ENST00000353468.4	TSL:1	n.*255G>T		non_coding_transcript_exon	Exon 4 of 4	ENSP00000434453.1	Q99720-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461880 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.7
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.031	D
Polyphen		0.88	P
Vest4		0.42
MutPred		0.71		Loss of methylation at R208 (P = 0.0071)
MVP		0.74
MPC		1.6
ClinPred		0.98	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.93
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs541996857; hg19: chr9-34635678;