rs11559048

Positions:

chr9-34635682-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 4.29

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIGMAR1	NM_005866.4 linkuse as main transcript	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 linkuse as main transcript	c.622C>T	p.Arg208Trp	missense_variant	4/4	1	NM_005866.4	P1	Q99720-1

Frequencies

GnomAD3 genomes

AF:

0.00870

AC:

1325

AN:

152220

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00697

AC XY:

947

AN XY:

135844

show subpopulations

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.:

Cov.:

AF XY:

0.00372

AC XY:

2702

AN XY:

727240

show subpopulations

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.:

Cov.:

AF XY:

0.00864

AC XY:

644

AN XY:

74496

show subpopulations

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.:

Bravo

AF:

0.0104

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.0177

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.00775

AC:

941

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.00229

EpiControl

AF:

0.00290

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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 -

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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

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

BayesDel_noAF

Benign

-0.23

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.73

.;D;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.97

D;D;D

MetaRNN

Benign

0.0082

T;T;T

MetaSVM

Uncertain

-0.25

MutationAssessor

Uncertain

2.4

.;M;.

MutationTaster

Benign

0.62

D;D;D

PrimateAI

Uncertain

0.60

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over