Variant 9-34635687-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_005866.4(SIGMAR1):c.617A>C(p.Tyr206Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SIGMAR1
NM_005866.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.74

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.778

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIGMAR1	NM_005866.4 linkuse as main transcript	c.617A>C	p.Tyr206Ser	missense_variant	4/4	ENST00000277010.9	NP_005857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIGMAR1	ENST00000277010.9 linkuse as main transcript	c.617A>C	p.Tyr206Ser	missense_variant	4/4	1	NM_005866.4	ENSP00000277010	P1	Q99720-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 2021

The p.Y206S variant (also known as c.617A>C), located in coding exon 4 of the SIGMAR1 gene, results from an A to C substitution at nucleotide position 617. The tyrosine at codon 206 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.67

.;D;.

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Uncertain

0.090

MetaRNN

Pathogenic

0.78

D;D;D

MetaSVM

Benign

-0.68

MutationAssessor

Benign

1.9

.;L;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-5.0

D;D;D

REVEL

Uncertain

0.50

Sift

Benign

0.53

T;T;T

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.77

MutPred

0.58

.;Gain of disorder (P = 0.023);.;

MVP

0.70

MPC

2.2

ClinPred

1.0

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.90

gMVP

0.99

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over