9-34637419-C-T

Position:

• chr9-34637419-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_005866.4(SIGMAR1):​c.153G>A​(p.Gly51=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00337 in 1,602,422 control chromosomes in the GnomAD database, including 155 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G51G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.018 (100 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (55 hom.)
• Consequence: SIGMAR1 NM_005866.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.0002048
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.53

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 9-34637419-C-T is Benign according to our data. Variant chr9-34637419-C-T is described in ClinVar as [Benign]. Clinvar id is 465867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-34637419-C-T is described in Lovd as [Likely_benign]. Variant chr9-34637419-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.53 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0607 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIGMAR1	NM_005866.4	c.153G>A	p.Gly51=	splice_region_variant, synonymous_variant	2/4	ENST00000277010.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIGMAR1	ENST00000277010.9	c.153G>A	p.Gly51=	splice_region_variant, synonymous_variant	2/4	1	NM_005866.4	P1

Frequencies

GnomAD3 genomes AF: 0.0183 AC: 2783 AN: 152240 Hom.: 100 Cov.: 33

Gnomad AFR AF: 0.0628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00805

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.00482 AC: 1100 AN: 228184 Hom.: 31 AF XY: 0.00353 AC XY: 444 AN XY: 125656

Gnomad AFR exome AF: 0.0634

Gnomad AMR exome AF: 0.00412

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000668

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000252

Gnomad OTH exome AF: 0.00347

GnomAD4 exome AF: 0.00180 AC: 2611 AN: 1450064 Hom.: 55 Cov.: 32 AF XY: 0.00150 AC XY: 1086 AN XY: 721718

Gnomad4 AFR exome AF: 0.0590

Gnomad4 AMR exome AF: 0.00429

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000582

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000138

Gnomad4 OTH exome AF: 0.00445

GnomAD4 genome AF: 0.0183 AC: 2790 AN: 152358 Hom.: 100 Cov.: 33 AF XY: 0.0175 AC XY: 1301 AN XY: 74506

Gnomad4 AFR AF: 0.0627

Gnomad4 AMR AF: 0.00804

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00222 Hom.: 9

Bravo AF: 0.0213

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 15, 2019	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

Autosomal recessive distal spinal muscular atrophy 2;C3280587:Amyotrophic lateral sclerosis type 16 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	12
DANN	Benign	0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00020
dbscSNV1_RF	Benign	0.016
SpliceAI score (max)		0.050		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: rs12115733; hg19: chr9-34637416;