rs541996857

Variant names:

• chr9-34635681-C-G
• rs541996857
• NM_005866.4:c.623G>C
• SIGMAR1 p.Arg208Pro

Your query was ambiguous. Multiple possible variants found:

• chr9-34635681-C-G
• chr9-34635681-C-T
• chr9-34635681-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005866.4(SIGMAR1):​c.623G>C​(p.Arg208Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). 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)
• Consequence: SIGMAR1 NM_005866.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• autosomal recessive distal spinal muscular atrophy 2

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.825

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>C	p.Arg208Pro	missense	Exon 4 of 4	NP_005857.1	Q99720-1
	SIGMAR1	NM_001282207.2		c.563G>C	p.Arg188Pro	missense	Exon 4 of 4	NP_001269136.1	Q99720-2
	SIGMAR1	NM_147157.3		c.530G>C	p.Arg177Pro	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>C	p.Arg208Pro	missense	Exon 4 of 4	ENSP00000277010.4	Q99720-1
	SIGMAR1	ENST00000477726.1	TSL:1	c.530G>C	p.Arg177Pro	missense	Exon 3 of 3	ENSP00000420022.1	Q99720-3
	SIGMAR1	ENST00000353468.4	TSL:1	n.*255G>C		non_coding_transcript_exon	Exon 4 of 4	ENSP00000434453.1	Q99720-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive distal spinal muscular atrophy 2;C3280587:Amyotrophic lateral sclerosis type 16 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	-0.081	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.7
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.024	D
Varity_R		0.99
gMVP		0.99
Mutation Taster		=68/32	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs541996857;

hg19: chr9-34635678;