9-34637693-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005866.4(SIGMAR1):c.5A>C(p.Gln2Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.175 in 1,526,870 control chromosomes in the GnomAD database, including 24,420 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q2Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.18 ( 2474 hom., cov: 33)

Exomes 𝑓: 0.17 ( 21946 hom. )

Consequence

SIGMAR1
NM_005866.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.168

Publications

53 publications found

Variant links:

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

SIGMAR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0011137724).

BP6

Variant 9-34637693-T-G is Benign according to our data. Variant chr9-34637693-T-G is described in ClinVar as Benign. ClinVar VariationId is 586584.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.3 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SIGMAR1	NM_005866.4	MANE Select	c.5A>C	p.Gln2Pro	missense	Exon 1 of 4	NP_005857.1
SIGMAR1	NM_001282207.2		c.5A>C	p.Gln2Pro	missense	Exon 1 of 4	NP_001269136.1
SIGMAR1	NM_147157.3		c.5A>C	p.Gln2Pro	missense	Exon 1 of 3	NP_671513.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SIGMAR1	ENST00000277010.9	TSL:1 MANE Select	c.5A>C	p.Gln2Pro	missense	Exon 1 of 4	ENSP00000277010.4
SIGMAR1	ENST00000477726.1	TSL:1	c.5A>C	p.Gln2Pro	missense	Exon 1 of 3	ENSP00000420022.1
SIGMAR1	ENST00000353468.4	TSL:1	n.5A>C		non_coding_transcript_exon	Exon 1 of 4	ENSP00000434453.1

Frequencies

GnomAD3 genomes

AF:

0.179

AC:

27181

AN:

152154

Hom.:

2475

Cov.:

show subpopulations

Gnomad AFR

AF:

0.184

Gnomad AMI

AF:

0.210

Gnomad AMR

AF:

0.225

Gnomad ASJ

AF:

0.137

Gnomad EAS

AF:

0.313

Gnomad SAS

AF:

0.192

Gnomad FIN

AF:

0.133

Gnomad MID

AF:

0.204

Gnomad NFE

AF:

0.162

Gnomad OTH

AF:

0.186

GnomAD2 exomes

AF:

0.201

AC:

25339

AN:

125854

AF XY:

0.197

show subpopulations

Gnomad AFR exome

AF:

0.182

Gnomad AMR exome

AF:

0.278

Gnomad ASJ exome

AF:

0.140

Gnomad EAS exome

AF:

0.315

Gnomad FIN exome

AF:

0.130

Gnomad NFE exome

AF:

0.166

Gnomad OTH exome

AF:

0.181

GnomAD4 exome

AF:

0.175

AC:

240232

AN:

1374600

Hom.:

21946

Cov.:

AF XY:

0.175

AC XY:

118299

AN XY:

677516

show subpopulations

African (AFR)

AF:

0.181

AC:

5631

AN:

31132

American (AMR)

AF:

0.268

AC:

9275

AN:

34626

Ashkenazi Jewish (ASJ)

AF:

0.139

AC:

3444

AN:

24796

East Asian (EAS)

AF:

0.313

AC:

11112

AN:

35454

South Asian (SAS)

AF:

0.192

AC:

15140

AN:

78666

European-Finnish (FIN)

AF:

0.131

AC:

4462

AN:

33978

Middle Eastern (MID)

AF:

0.172

AC:

808

AN:

4710

European-Non Finnish (NFE)

AF:

0.168

AC:

180438

AN:

1073896

Other (OTH)

AF:

0.173

AC:

9922

AN:

57342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

10371

20742

31114

41485

51856

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6700

13400

20100

26800

33500

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.178

AC:

27180

AN:

152270

Hom.:

2474

Cov.:

AF XY:

0.179

AC XY:

13308

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.184

AC:

7630

AN:

41562

American (AMR)

AF:

0.225

AC:

3433

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.137

AC:

477

AN:

3472

East Asian (EAS)

AF:

0.313

AC:

1619

AN:

5170

South Asian (SAS)

AF:

0.192

AC:

927

AN:

4832

European-Finnish (FIN)

AF:

0.133

AC:

1407

AN:

10618

Middle Eastern (MID)

AF:

0.192

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.162

AC:

11051

AN:

68016

Other (OTH)

AF:

0.184

AC:

389

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1200

2400

3601

4801

6001

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

298

596

894

1192

1490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.161

Hom.:

403

Bravo

AF:

0.188

TwinsUK

AF:

0.162

AC:

601

ALSPAC

AF:

0.173

AC:

667

ESP6500AA

AF:

0.134

AC:

472

ESP6500EA

AF:

0.116

AC:

752

ExAC

AF:

0.0809

AC:

3361

Asia WGS

AF:

0.256

AC:

890

AN:

3468

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:3

Nov 17, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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: 31159747, 30917570, 21549171, 22818711, 9857962, 22561649)

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Autosomal recessive distal spinal muscular atrophy 2

Benign:1

May 28, 2019

Mendelics

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.091

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.54

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.75

MetaRNN

Benign

0.0011

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.55

PhyloP100

0.17

PrimateAI

Uncertain

0.66

PROVEAN

Benign

0.030

REVEL

Benign

0.14

Sift

Benign

0.34

Sift4G

Benign

0.43

Polyphen

0.0

Vest4

0.11

MPC

0.96

ClinPred

0.00034

GERP RS

0.91

PromoterAI

0.026

Neutral

(source)

Varity_R

0.42

gMVP

0.54

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over