rs11559048

chr9-34635682-G-A

Variant summary

Our verdict is Benign. Variant got -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:5
• Conservation: PhyloP100: 4.29

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 465871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-34635682-G-A is described in Lovd as [Likely_benign]. Variant chr9-34635682-G-A is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIGMAR1	NM_005866.4	c.622C>T	p.Arg208Trp	missense_variant	4/4	ENST00000277010.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIGMAR1	ENST00000277010.9	c.622C>T	p.Arg208Trp	missense_variant	4/4	1	NM_005866.4	P1

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

GnomAD3 exomes AF: 0.00782 AC: 1966 AN: 251282 Hom.: 26 AF XY: 0.00697 AC XY: 947 AN XY: 135844

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 SAS exome AF: 0.00438

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

Gnomad4 AFR exome AF: 0.0211

Gnomad4 AMR exome AF: 0.0161

Gnomad4 ASJ exome AF: 0.00287

Gnomad4 EAS exome AF: 0.0299

Gnomad4 SAS exome AF: 0.00477

Gnomad4 FIN exome AF: 0.00152

Gnomad4 NFE exome AF: 0.00183

Gnomad4 OTH exome AF: 0.00508

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

Gnomad4 AFR AF: 0.0188

Gnomad4 AMR AF: 0.00934

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.0286

Gnomad4 SAS AF: 0.00600

Gnomad4 FIN AF: 0.00348

Gnomad4 NFE AF: 0.00232

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00452 Hom.: 6

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

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 07, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 17, 2020	This variant is associated with the following publications: (PMID: 31159747, 31324122, 30311446, 25174650, 29411640) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	SIGMAR1: BS1, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 31, 2020

- -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.97	D;D;D
MetaRNN	Benign	0.0082	T;T;T
MetaSVM	Uncertain	-0.25	T
MutationTaster	Benign	0.62	D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-4.0	D;D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.011	D;D;D
Sift4G	Uncertain	0.0050	D;D;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs11559048; hg19: chr9-34635679;