9-34635682-G-A

Variant names:

• chr9-34635682-G-A
• rs11559048
• NM_005866.4:c.622C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005866.4(SIGMAR1):​c.622C>T​(p.Arg208Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00425 in 1,614,216 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R208P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0087 (17 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (47 hom.)
• Consequence: SIGMAR1 NM_005866.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.29
• Publications: 18 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008241296).
• BP6: Variant 9-34635682-G-A is Benign according to our data. Variant chr9-34635682-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 465871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0087 (1325/152338) while in subpopulation EAS AF = 0.0286 (148/5176). AF 95% confidence interval is 0.0248. There are 17 homozygotes in GnomAd4. There are 644 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

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.622C>T	p.Arg208Trp	missense	Exon 4 of 4	NP_005857.1
	SIGMAR1	NM_001282207.2		c.562C>T	p.Arg188Trp	missense	Exon 4 of 4	NP_001269136.1
	SIGMAR1	NM_147157.3		c.529C>T	p.Arg177Trp	missense	Exon 3 of 3	NP_671513.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIGMAR1	ENST00000277010.9	TSL:1 MANE Select	c.622C>T	p.Arg208Trp	missense	Exon 4 of 4	ENSP00000277010.4
	SIGMAR1	ENST00000477726.1	TSL:1	c.529C>T	p.Arg177Trp	missense	Exon 3 of 3	ENSP00000420022.1
	SIGMAR1	ENST00000353468.4	TSL:1	n.*254C>T		non_coding_transcript_exon	Exon 4 of 4	ENSP00000434453.1

Frequencies

GnomAD3 genomes AF: 0.00870 AC: 1325 AN: 152220 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00936

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.0285

Gnomad SAS AF: 0.00620

Gnomad FIN AF: 0.00348

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00232

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00782 AC: 1966 AN: 251282 AF XY: 0.00697

Gnomad AFR exome AF: 0.0195

Gnomad AMR exome AF: 0.0169

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.0308

Gnomad FIN exome AF: 0.00157

Gnomad NFE exome AF: 0.00229

Gnomad OTH exome AF: 0.00652

GnomAD4 exome AF: 0.00379 AC: 5539 AN: 1461878 Hom.: 47 Cov.: 36 AF XY: 0.00372 AC XY: 2702 AN XY: 727240

African (AFR) AF: 0.0211 AC: 705 AN: 33478

American (AMR) AF: 0.0161 AC: 718 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00287 AC: 75 AN: 26136

East Asian (EAS) AF: 0.0299 AC: 1186 AN: 39700

South Asian (SAS) AF: 0.00477 AC: 411 AN: 86254

European-Finnish (FIN) AF: 0.00152 AC: 81 AN: 53418

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5768

European-Non Finnish (NFE) AF: 0.00183 AC: 2040 AN: 1112008

Other (OTH) AF: 0.00508 AC: 307 AN: 60394

GnomAD4 genome AF: 0.00870 AC: 1325 AN: 152338 Hom.: 17 Cov.: 32 AF XY: 0.00864 AC XY: 644 AN XY: 74496

African (AFR) AF: 0.0188 AC: 781 AN: 41580

American (AMR) AF: 0.00934 AC: 143 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3470

East Asian (EAS) AF: 0.0286 AC: 148 AN: 5176

South Asian (SAS) AF: 0.00600 AC: 29 AN: 4832

European-Finnish (FIN) AF: 0.00348 AC: 37 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00232 AC: 158 AN: 68034

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00527 Hom.: 22

Bravo AF: 0.0104

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.0177 AC: 78

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.00775 AC: 941

Asia WGS AF: 0.0120 AC: 41 AN: 3478

EpiCase AF: 0.00229

EpiControl AF: 0.00290

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Autosomal recessive distal spinal muscular atrophy 2;C3280587:Amyotrophic lateral sclerosis type 16 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0082	T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.3
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.39
MVP		0.80
MPC		1.9
ClinPred		0.024	T
GERP RS		3.5
Varity_R		0.78
gMVP		0.95
Mutation Taster		=94/6	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: rs11559048; hg19: chr9-34635679; COSMIC: COSV107315734; COSMIC: COSV107315734;