Genetic Variant SIGMAR1:p.Gly139Asp (chr9-34637026-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_005866.4(SIGMAR1):c.416G>A(p.Gly139Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G139V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

SIGMAR1
NM_005866.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.70

Publications

1 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.929

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	UniProt
SIGMAR1	NM_005866.4	MANE Select	c.416G>A	p.Gly139Asp	missense	Exon 3 of 4	NP_005857.1	Q99720-1
SIGMAR1	NM_001282207.2		c.356G>A	p.Gly119Asp	missense	Exon 3 of 4	NP_001269136.1	Q99720-2
SIGMAR1	NM_001282208.2		c.439G>A	p.Ala147Thr	missense	Exon 3 of 4	NP_001269137.1	A0A7P0Z4C2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SIGMAR1	ENST00000277010.9	TSL:1 MANE Select	c.416G>A	p.Gly139Asp	missense	Exon 3 of 4	ENSP00000277010.4	Q99720-1
SIGMAR1	ENST00000477726.1	TSL:1	c.352+194G>A		intron	N/A	ENSP00000420022.1	Q99720-3
SIGMAR1	ENST00000353468.4	TSL:1	n.*48G>A		non_coding_transcript_exon	Exon 3 of 4	ENSP00000434453.1	Q99720-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251176

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.087

MetaRNN

Pathogenic

0.93

MetaSVM

Uncertain

0.20

MutationAssessor

Uncertain

2.9

PhyloP100

7.7

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-5.7

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.035

Polyphen

0.84

Vest4

0.78

MutPred

0.83

Gain of solvent accessibility (P = 0.0638)

MVP

0.77

MPC

2.1

ClinPred

0.99

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.96

Mutation Taster

=7/93

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over